NCCN guidelines on Breast cancer

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NCCN Clinical Practice Guidelines in Oncology™

Breast CancerV.2.2007

www.nccn.org

Version 2.2007, 03/28/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN® Practice Guidelines

in Oncology – v.2.2007

Guidelines Index

Breast Cancer TOC

Staging, MS, References

NCCN Breast Cancer Panel Members

Robert W. Carlson, MD/Chair †Stanford Hospital and Clinics

William J. Gradishar, MD ‡Robert H. Lurie Comprehensive CancerCenter of Northwestern University

Daniel F. Hayes, MD †University of Michigan ComprehensiveCancer Center

Benjamin O. Anderson, MD ¶Fred Hutchinson Cancer ResearchCenter/Seattle Cancer Care Alliance

Harold J. Burstein, MD, PhD †Dana-Farber/Partners CancerCare

W. Bradford Carter, MD ¶H. Lee Moffitt Cancer Center & ResearchInstitute at the University of South Florida

Stephen B. Edge, MD ¶Roswell Park Cancer Institute

William B. Farrar, MD ¶Arthur G. James Cancer Hospital & RichardJ. Solove Research Institute at The OhioState University

Lori J. Goldstein, MD †Fox Chase Cancer Center

Elizabeth C. Reed, MD †UNMC Eppley Cancer Center at TheNebraska Medical Center

Samuel M. Silver, MD, PhD ‡University of Michigan ComprehensiveCancer Center

Mary Lou Smith, JD, MBA ¥Consultant

George Somlo, MD ‡City of Hope Cancer Center

Richard L. Theriault, DO, MBA †The University of Texas M. D. AndersonCancer Center

John H. Ward, MD ‡Huntsman Cancer Institute at theUniversity of Utah

Eric P. Winer, MD †Dana-Farber/Partners CancerCare

Antonio C. Wolff, MD †The Sidney Kimmel ComprehensiveCancer Center at Johns HopkinsUniversity

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Clifford A. Hudis, MD †Memorial Sloan-Kettering Cancer Center

Mohammad Jahanzeb, MD ‡St. Jude Children’s Research Hospital/University of Tennessee Cancer Institute

Britt-Marie Ljung, MDUCSF Comprehensive Cancer Center

Krystyna Kiel, MDRobert H. Lurie Comprehensive CancerCenter of Northwestern University

Lawrence B. Marks, MD §Duke Comprehensive Cancer Center

Beryl McCormick, MD §Memorial Sloan-Kettering Cancer Center

Lisle M. Nabell, MD ‡University of Alabama at BirminghamComprehensive Cancer Center

Lori J. Pierce, MD §University of Michigan ComprehensiveCancer Center

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† Medical Oncology‡ Hematology/Oncology¶ Surgical Oncology

Pathology�

§ Radiation Oncology

Bone Marrow Transplantation¥ Patient Advocacy* Writing Committee Member

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Continue

Breast Cancer

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Guidelines Index

Breast Cancer TOC


Table of Contents

Noninvasive Breast Cancer

Invasive Breast Cancer

NCCN Breast Cancer Panel Members

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Lobular Carcinoma In Situ (LCIS-1)

Ductal Carcinoma In Situ (DCIS-1)

Clinical Stage, Workup (BINV-1)

Locoregional Treatment of Clinical Stage l, llA,or llB Disease or T3,N1,M0 (BINV-2)

Systemic Adjuvant Treatment (BINV-4)

Preoperative Chemotherapy Guideline

Clinical Stage llA, llB, Workup (BINV-10)

Primary Treatment, Adjuvant Treatment(BINV-11)

Clinical Stage lllA, lllB, lllC, and Stage IV,Workup (BINV-13)

Preoperative Chemotherapy, LocoregionalTreatment, Adjuvant Treatment (BINV-14)

Surveillance/Follow-Up, Recurrence Workup or

Initial Workup for Stage lV Disease (BINV-15)

Treatment of Recurrence/Stage IV Disease

(BINV-16)

Follow-up Therapy for Hormone Treatment of

Recurrence/Stage IV (BINV-17)

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These guidelines are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinicianseeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances todetermine any patient's care or treatment. The National Comprehensive Cancer Network makes no representations nor warranties of any kindwhatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. These guidelines arecopyrighted by National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced inany form without the express written permission of NCCN. ©2007.

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Guidelines Index

Print the Breast Cancer Guideline

Order the Patient Version of the

Breast Cancer Guideline

Staging

Manuscript

References

Clinical Trials:

Categories of Consensus:NCCN

Thebelieves that the best managementfor any cancer patient is in a clinicaltrial. Participation in clinical trials isespecially encouraged.

To find clinical trials online at NCCNmember institutions,

All recommendations are Category2A unless otherwise specified.

See

NCCN

click here:nccn.org/clinical_trials/physician.html

NCCN Categories of Consensus

Summary of Guidelines Updates

Invasive Breast Cancer (continued)

Special Considerations

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Principles of HER2 Testing (BINV-A)

Principles of Dedicated Breast MRI

Testing (BINV-B)

Surgical Axillary Staging - Stage l, llA ,

and llB (BINV-C)

Axillary Lymph Node Staging (BINV-D)

Margin Status in Infiltrating Carcinoma(BINV-E)

Special Considerations to Breast-Conserving Therapy Requiring RadiationTherapy (BINV-F)

Adjuvant Hormonal Therapy (BINV-G)

Adjuvant Chemotherapy (BINV-H)

Definition of Menopause (BINV-I)

Subsequent Hormonal Therapy (BINV-J)

Preferred Chemotherapy Regimens forRecurrent or Metastatic Breast Cancer(BINV-K)

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Phyllodes Tumor (PHYLL-1)

Paget’s Disease (PAGET-1)

Breast Cancer During Pregnancy

(PREG-1)

Breast Cancer

http://www.nccn.org/clinical_trials/physician.html




Guidelines Index

Breast Cancer TOC


Summary of the Guidelines Updates

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

UPDATES

Breast Cancer

Summary of changes in the 2.2007 version of the Breast Guidelines from the 1.2007 version include:

� Based on FDA approval and data from a recent Phase lll study of lapatinib plus capecitabine for HER2 positive advanced breast cancer, the

Panel added the following footnote for patients with HER2-positive breast cancer that is hormone receptor-negative, symptomatic visceral

disease, or hormone refractory ( ):

"Lapatinib plus capecitabine is an option in patients previously treated with an anthracycline, taxane, and trastuzumab."

See BINV-16

Summary changes in the 1.2007 version of the Breast Guidelines from the 2.2006 version include:

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Based on results from the NSABP Study of Tamoxifen and Raloxifene (STAR) trial, the Panel added raloxifene as an option for reducing the

risk of invasive breast cancer in postmenopausal women with lobular carcinoma in situ .

Footnotes c and d are new to page .

Margin status in DCIS ( With respect to p

The accuracy of HER2 assays used in clinical practice is a major concern, and results from several studies have shown that false-positive

and false-negative HER2 test results are common. An NCCN Task Force reviewed this topic and issued recommendations which are

summarized in the Principles of HER2 Testing ).

When breast MRI is indicated, it should be performed and interpreted by a expert breast imaging team working in concert with the

multidisciplinary treatment team. The Panel recommendations for breast MRI testing are listed on page .

Sentinel node mapping and excision is now listed as preferred over axillary dissection level l/ll ( ).

Footnote 5 is new to page .

Sentinel lymph node biopsy is the preferred method of axillary lymph node staging ( ).

Aromatase inhibitors are not active in the treatment of women with functioning ovaries and should not be used in women with intact ovarian

function. The assessment of ovarian function in women experiencing treatment-induced amenorrhea is difficult and requires re-evaluation

over time. This has been elaborated in the Definition of Menopause ( .

( )

(

)

See LCIS-1

LCIS-1

See DCIS-A).

See BINV-A

BINV-B

See BINV-C

BINV-C

See BINV-D

See BINV-I

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athologic margins between 1-10 mm, wider margins are generally associated with lower

local recurrence rates. However, close surgical margins (< 1mm) at the fibroglandular boundary of the breast (chest wall or skin) do not

mandate surgical re-excission but can be an indication for higher boost dose radiation to the involved lumpectomy site. (category 2B)

Have an increased risk of ipsilateral breast recurrence or contralateral breast cancer with breast conserving therapyProphylactic bilateral mastectomy for risk reduction may be considered.

Recent studies document the substantial improvement in outcome with the incorporation of trastuzumab in adjuvant treatment of HER2

positive breast cancer The guideline includes specific representative doses and schedules for the recommended adjuvant chemotherapy

regimens ( ). A number of chemotherapy regimens have been studied as preoperative chemotherapy. The Panel believes that the

regimens listed in the adjuvant setting are also appropriate to consider in the neoadjuvant setting.

Treatment of recurrence ( ± hyperthermia was added as a category 3 recommendation.

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Special considerations to breast-conserving therapy requiring radiation therapy ( ) has been updated to include the following

relative contraindication: Women 35 y or premenopausal women with a known BRCA 1/2 mutation:��

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See BINV-F

See BINV-H

See BINV-16)




Guidelines Index

Breast Cancer TOC




WORKUPDIAGNOSIS PRIMARYTREATMENT

RISK REDUCTION SURVEILLANCE/FOLLOW-UP

Lobular carcinomain situ (LCIS)Stage 0Tis, N0, M0a

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H&P

Diagnostic bilateral

mammogram

Pathology reviewb

Observationc

Counseling regarding riskreduction with tamoxifen forpremenopausal women, orwith tamoxifen or raloxifenefor postmenopausal women(category 1, see also

orIn special circumstances,bilateral mastectomy ±reconstruction may beconsidered for risk reduction

d

NCCNBreast Cancer RiskReduction Guidelines)

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Interval history and physicalexam every 6-12 moMammogram every 12 mo,unless postbilateralmastectomyIf treated with tamoxifen,monitor per NCCN BreastCancer Risk ReductionGuidelines

a

b

c

d

The panel endorses the College of American Pathology Protocol for pathology reporting for all invasive and non-invasive carcinomas of the breast.

Histologically aggressive va iants of LCIS (pleomorphic LCIS) may have a si i ar biological behavior to that of DCIS, but outcome data regarding the efficacy ofsurgical excision to negative margins and/or radiotherapy are lacking.

Some serotonin reuptake inhibitors decrease the formation of endoxifen, an active metabolite of tamoxifen. However, citalopram and venlafaxine appear to haveminimal impact on tamoxifen metabolism. The clinical impact of these observations is not known.

r m l

See NCCN Breast Cancer Screening and Diagnosis Guidelines.

http://www.cap.org/apps/docs/cancer_protocols/protocols_index.html

LCIS-1

Lobular Carcinoma in Situ





Guidelines Index

Breast Cancer TOC




WORKUPDIAGNOSIS

Ductal carcinomain situ (DCIS)Stage 0Tis, N0, M0a

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H&P

Diagnostic bilateral

mammogram

Pathology review

Determination of tumor

estrogen receptor (ER)

status

b

DCIS-1

a

c

d

bThe panel endorses the College of American Pathology Protocol for pathologyreporting for all invasive and non-invasive carcinomas of the breast.

Re-resection(s) may be performed in an effort to obtain negative margins inpatients desiring breast conserving therapy. Patients not amenable to margin-freelumpectomy should have total mastectomy.

e

f

g

Whole breast irradiation with boost (by photons, brachytherapy or electron beam)to tumor bed. Boost to tumor bed is especially encouraged in those 50 y of age oryounger. Partial breast irradiation should be performed only as part of a highquality prospective clinical trial.

Long-term survival with mastectomy versus excision and irradiation appears to beequivalent.

Complete resection should be documented by analysis of margins, specimenmammography and where appropriate post-excision mammography.

See NCCN Breast Cancer Screening and Diagnosis Guidelines.


See Margin Status in DCIS (DCIS-A).

PRIMARY TREATMENT

Lumpectomy without lymph node

dissection + RT

or

Total mastectomy without lymph

node dissection ± reconstruction

c,d

f,h,k

k e,f,g,h,i,j

Small (< 0.5 cm),unicentric, lowgrade

Lumpectomy + RT

or

Total mastectomy without lymph node

dissection ± reconstruction

or

Lumpectomy alone (category 2B)

c,d,k e,f,g,h,i,j

f,h,k

c,d,g,h,i,j,k

hPatients found to have invasive disease at total mastectomy or re-excision shouldbe managed as stage l or stage ll disease, including lymph node staging.

i

j

k

).

Prospective studies have demonstrated that whole breast radiation lowers the riskof ipsilateral invasive breast cancer recurrence following excision of DCIS. Somepatients may be treated with excision alone, particularly if a patient is willing toaccept a higher risk of local recurrence. Other factors that should be consideredinclude patient age, comorbidity, tumor margins and tumor grade.

Axillary lymph node staging is discouraged in women with apparent pure DCIS.However, a small proportion of patients with apparent pure DCIS will be found tohave invasive cancer at the time of their definitive surgical procedure. Therefore,the performance of a sentinel lymph node procedure may be considered if thepatient with apparent pure DCIS is to be treated with mastectomy or with excisionin an anatomic location compromising the performance of a future sentinel lymphnode procedure.

See Special Considerations Breast-Conserving Therapy (BINV-F

SeePostsurgicalTreatment(DCIS-2)

Ductal Carcinoma in Situ





Guidelines Index

Breast Cancer TOC




SURVEILLANCE/FOLLOW-UP

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Interval history and physical exam every 6 mofor 5 y, then annuallyMammogram every 12 moIf treated with tamoxifen, monitor per NCCNBreast Cancer Risk Reduction Guidelines

Adjuvant treatment:Consider tamoxifen for 5 years for:

Patients treated with breast-conserving therapy(lumpectomy) and RT (category 1)

Patients treated with excision alone

Risk reduction therapy:Counseling regarding consideration of tamoxifenfor risk reduction (category 2B).

l

m

m

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, especially forthose with ER-positive DCIS. The benefit oftamoxifen for ER-negative DCIS is uncertain

See also NCCNBreast Cancer Risk Reduction Guidelines

DCIS POSTSURGICAL TREATMENT

lSome serotonin reuptake inhibitors decrease the formation of endoxifen, an active metabolite of tamoxifen. However, citalopram and venlafaxine appear to haveminimal impact on tamoxifen metabolism. The clinical impact of these observations is not known.

mAvailable data suggest tamoxifen provides risk reduction in the ipsilateral breast treated with breast conservation and in the contralateral breast in patients withmastectomy or breast conservation with ER-positive primary tumors. Since a survival advantage has not been demonstrated, individual consideration of risks andbenefits is important ( ).See also NCCN Breast Cancer Risk Reduction Guidelines

DCIS-2





Guidelines Index

Breast Cancer TOC




MARGIN STATUS IN DCIS

Substantial controversy exists regarding the definition of a negative pathologicmargin in DCIS. Controversy arises out of the heterogeneity of the disease, difficultiesin distinguishing the spectrum of hyperplastic conditions, anatomic considerations ofthe location of the margin, and inadequate prospective data on prognostic factors inDCIS. Margins greater than 10 mm are widely accepted as negative (but may be excessiveand may lead to a less optimal cosmetic outcome). Margins less than 1 mmare considered inadequate. With pathologic margins between 1-10 mm, wider margins aregenerally associated with lower local recurrence rates. However, close surgical margins (<1mm) at the fibroglandular boundary of the breast (chest wall or skin) do not mandate surgicalre-excission but can be an indication for higher boost dose radiation to the involvedlumpectomy site. (category 2B)

DCIS-A





Guidelines Index

Breast Cancer TOC




CLINICAL STAGE WORKUP

Stage I

T1, N0, M0

or

Stage IIA

T0, N1, M0

T1, N1, M0

T2, N0, M0

or

Stage IIB

T2, N1, M0

T3, N0, M0

or

T3, N1, M0

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H&PCBC, plateletsLiver function testsChest imagingDiagnostic bilateral mammogram, ultrasound as necessaryPathology reviewDetermination of tumor estrogen/progesterone receptor (ER/PR)status and HER2 statusBreast MRI (optional)Bone scan (optional) (Indicated if localized symptoms or elevatedalkaline phosphatase or if T3, N1, M0) (category 2B)Abdominal CT or US or MRI (optional for stage llA or llB, indicated ifelevated alkaline phosphatase, abnormal LFTs, abdominalsymptoms, abnormal physical examination of the abdomen, or if T3,N1, M0) (category 2B)

a

b

c

See LocoregionalTreatment(BINV-2)

BINV-1

aThe panel endorses the College of American Pathology Protocol for pathology reporting for all invasive and non-invasive carcinomas of the breast.

b

c


See Principles of HER2 Testing (BINV-A

See Principles of Dedicated Breast MRI Testing (BINV-B

).

).






Guidelines Index

Breast Cancer TOC


LOCOREGIONAL TREATMENT OF CLINICAL STAGE I, IIA, OR IIB DISEASE OR T3, N1, M0

d

j

e

f

g

i

and

Consideration may be given to additional staging including bone scan and abdominal CT/US/MRI; chest CT (category 2B).

RT should be given to the internal mammary lymph nodes if they are clinically or pathologically positive, otherwise the treatment to the internal mammary nodes is atthe discretion of the treating radiation oncologist. CT treatment planning should be utilized in all cases where RT is delivered to the internal mammary lymph nodes.

Breast irradiation may be omitted in those 70 y of age or older with estrogen-receptor positive, clinically node negative, T1 tumors who receive adjuvant hormonaltherapy (category 1).

.

hWhole breast irradiation with boost (by photons, brachytherapy or electron beam) to tumor bed. Boost to tumor bed is especially encouraged in those 50 y of age oryounger. Partial breast irradiation should be performed only as part of a high quality prospective clinical trial.

See Surgical Axillary Staging (BINV-C

See Axillary Lymph Node Staging (BINV-D) Margin Status in Infiltrating Carcinoma (BINV-E)

See Special Considerations to Breast-Conserving Therapy (BINV-F).

).

Lumpectomy with surgicalaxillary staging (category 1)d,e,f

1-3 positivenodesaxillary

Negativenodes

axillary

RT to whole breast with boost (by photons, brachytherapy,

or electron beam) to tumor bed and supraclavicular area

(category 1). Consider RT to internal mammary nodes

(category 3). RT may be given concurrent with CMF (category

2B) or follow chemotherapy when chemotherapy indicated.

h

i

RT to whole breast with boost (by photons, brachytherapy,or electron beam) to tumor bed (category 1). Consider RT tosupraclavicular area (category 2B). Consider RT to internalmammary nodes (category 3). RT may be given concurrentwith CMF (category 2B) or follow chemotherapy whenchemotherapy indicated.

h

i

RT to whole breast with boost (by photons, brachytherapy,or electron beam) to tumor bed. RT may be givenconcurrent with CMF (category 2B) or follow chemotherapywhen chemotherapy indicated.

h

j

Total mastectomy with surgicalaxillary staging (category 1)± reconstruction

d,e

Consider Preoperative Chemotherapy Guideline (BINV-10)If T2 or T3 and fulfills criteria for breastconserving therapy except for sizef

See Locoregional Treatment (BINV-3)

or

or

BINV-2

� 4 positive

axillary nodesg

See BINV-4







Guidelines Index

Breast Cancer TOC




Total mastectomywith surgical axillarystaging (category1) ± reconstruction

d,e

LOCOREGIONAL TREATMENT OF CLINICAL STAGE I, IIA, OR IIB DISEASE OR T3, N1, M0

� 4 positive

axillary nodesg

Postchemotherapy RT to chest wall +supraclavicular area (category 1). Consider RT tointernal mammary nodes (category 3)i

1-3 positivenodesaxillary

Consider postchemotherapy RT to chest wall +supraclavicular area (category 1) ; if RT is given,consider internal mammary RT (category 3).

k

i

Negative axillary nodesand tumor > 5 cmormargins positive

Postchemotherapy RT to chest wall. Consider RTto supraclavicular area (category 2B) Consider RTto internal mammary nodes (category 3).i

Negative nodesand tumor 5 cm andmargins 1mm

axillary�

�No RT

d

e

i

.

and

RT should be given to the internal mammary lymph nodes that are clinically or pathologically positive, otherwise the treatment to the internal mammary nodes is at thediscretion of the treating radiation oncologist. CT treatment planning should be utilized in all cases where RT is delivered to the internal mammary lymph nodes

g

k

Consideration may be given to additional staging including bone scan; abdominal CT/US/MRI; chest CT (category 2B).

There is inconsistent high-level evidence of survival benefit in this subset.

See Surgical Axillary Staging (BINV-C

See Axillary Lymph Node Staging (BINV-D Margin Status in Infiltrating Carcinoma (BINV-E

).

) ).

Negative nodesand tumor 5 cm and

axillary

margins close (< 1mm)� Consider RT to chest wall

BINV-3

See BINV-4





Guidelines Index

Breast Cancer TOC


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Ductal, NOS

Lobular

Mixed

Metaplastic

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Tubular

Colloid

ER-positive

and/or

PR positive

ER-negative

and

PR-negative

ER-positive

and/or

PR positive

ER-negative

and

PR-negative

HER2 positiveb

HER2 negativeb

HER2 positiveb

HER2 negativeb

BINV-4

See Systemic Adjuvant Treatment - Hormone ReceptorPositive - HER2 Positive Disease (BINV-5)



bSee Principles of HER2 Testing (BINV-A).

See Systemic Adjuvant Treatment - HormoneReceptor Positive - HER2 Negative Disease (BINV-6)

See Systemic Adjuvant Treatment - HormoneReceptor Negative - HER2 Positive Disease (BINV-7)

See Systemic Adjuvant Treatment - HormoneReceptor Negative - HER2 Negative Disease (BINV-8)

See Systemic Adjuvant Treatment -Favorable Histologies (BINV-9)

HISTOLOGY HER2 STATUS SYSTEMIC ADJUVANT TREATMENTHORMONE

RECEPTOR STATUS





Guidelines Index

Breast Cancer TOC




BINV-5

See Follow-Up (BINV-15)

See Adjuvant Hormonal Therapy (BINV-G) Adjuvant Chemotherapy (BINV-H)and

Tumor > 1 cm

SYSTEMIC ADJUVANT TREATMENT - HORMONE RECEPTOR POSITIVE - HER2 POSITIVE DISEASEb

Histology:Ductal, NOSLobularMixedMetaplastic

l

��

ER-positiveand/orPR-positiveandHER2positive

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Tumor 0.5 cm or

Microinvasive or

Tumor 0.6-1.0 cm, well differentiated

�

Tumor 0.6-1.0 cm, moderate/poorlydifferentiated or unfavorable featuresm

pN0

pN1mi

Adjuvant hormonal therapy

± adjuvant chemotherapy

(category 1)

p

o,q,r,s

pT1, pT2, or pT3;

and pN0 or pN1mi

( 2 mm axillary

node metastasis)

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No adjuvant therapyn

Consider adjuvant

hormonal therapyo,p,s


+ adjuvant chemotherapy +

trastuzumab (category 1)

p

o,q,r,s


+ adjuvant chemotherapy +

trastuzumab (category 1)

p

o,q,r

Node positive (one or more

metastases > 2 mm to one

or more ipsilateral axillary

lymph nodes)

b

s

.

Evidence supports that the magnitude of benefit from surgical or radiation ovarian ablation in premenopausal women with hormone-receptor-positive breast cancer issimilar to that achieved with CMF alone. Early evidence suggests similar benefits from ovarian suppression (ie, LHRH agonist or antagonist) as from ovarian ablation.The combination of ovarian ablation/suppression plus hormonal therapy may be superior to suppression alone. The benefit of ovarian ablation/suppression inpremenopausal women who have received adjuvant chemotherapy is uncertain.

There are insufficient data to make chemotherapy recommendations for those over 70 y old. Treatment should be individualized with consideration of comorbidconditions.

Limited data support that a 21 gene RT-PCR assay (Onco DX) may provide both prognostic information and prediction of benefit, or lack thereof, fromchemotherapy in women with axillary lymph node negative, hormone receptor-positive breast cancer treated with tamoxifen. The panel awaits additional studies priorto issuing a specific recommendation regarding this or similar assays (such as MammaPrint).

l

m

n

q

Mixed lobular and ductal carcinoma as well as metaplastic carcinoma should be graded based on the ductal component and treated based on this grading. Themetaplastic or mixed component does not alter prognosis.

Unfavorable features: angiolymphatic invasion, high nuclear grade, or high histologic grade.

If ER-positive consider hormonal therapy for risk reduction and to diminish the small risk of disease recurrence.

Chemotherapy and hormonal therapy used as adjuvant therapy should be given sequentially with hormonal therapy following chemotherapy. The benefits ofchemotherapy and of hormonal therapy are additive. However, the absolute benefit from chemotherapy may be small. The decision to add chemotherapy to hormonal

therapy should be individualized, especially in those with a favorable prognosis and in women age 60 y where the incremental benefit of chemotherapy may besmaller. Available data suggest sequential or concurrent hormonal therapy with RT is acceptable.

o

p

r

�

type

See Principles of HER2 Testing (BINV-A)

See Adjuvant Hormonal Therapy (BINV-G).





Guidelines Index

Breast Cancer TOC


Tumor > 1 cm




SYSTEMIC ADJUVANT TREATMENT - HORMONE RECEPTOR POSITIVE - HER2 NEGATIVE DISEASEb


l

��

ER-positiveand/orPR-positiveandHER2negative

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Tumor 0.5 cm or

Microinvasive or

Tumor 0.6-1.0 cm, well differentiated,no unfavorable features

�

m

Tumor 0.6-1.0 cm, moderate/poorlydifferentiated or unfavorable featuresm

pN0

pN1mi



(category 1)

p

o,q,r,s

BINV-6

pT1, pT2, or pT3;

and pN0 or pN1mi

( 2 mm axillary

node metastasis)

�


Consider adjuvant

hormonal therapyo,p,s



(category 1)

p

o,q,r,s


+ adjuvant chemotherapy

(category 1)

p

o,q,r


metastases > 2 mm to one

or more ipsilateral axillary

lymph nodes)

See Adjuvant Hormonal Therapy (BINV-G) Adjuvant Chemotherapy (BINV-H)andb

s

.



Limited data support that a 21 gene RT-PCR assay (Onco DX) may provide both prognostic information and prediction of benefit, or lack thereof, fromchemotherapy in women with axillary lymph node negative, hormone receptor-positive breast cancer treated with tamoxifen. The panel awaits additional studies priorto issuing a specific recommendation regarding this or similar assays (such as MammaPrint).

l

m

n

q


Unfavorable features: angiolymphatic invasion, high nuclear grade, or high histologic grade.




o

p

r

�

type







Guidelines Index

Breast Cancer TOC


ER-negativeandPR-negativeandHER2

positive

Consider chemotherapyr



BINV-7

SYSTEMIC ADJUVANT TREATMENT - HORMONE RECEPTOR NEGATIVE - HER2 POSITIVE DISEASEb

Tumor > 1 cmHistology:

Ductal, NOSLobularMixedMetaplastic

l

��

�

�

Tumor 0.5 cm or

Microinvasive

�

Tumor 0.6-1.0 cm

pN0

pN1mi

pT1, pT2, or pT3; pN0

or pN1mi ( 2 mm axillary

node metastasis)

and

�

No adjuvant therapy

Consider chemotherapy

(category 1)r

Adjuvant chemotherapy

+ trastuzumab (category 1)

r


+ trastuzumab (category 1)

r

b .


l

r







metastases > 2 mm to one or more

ipsilateral axillary lymph nodes)




Guidelines Index

Breast Cancer TOC


SYSTEMIC ADJUVANT TREATMENT - HORMONE RECEPTOR NEGATIVE - HER2 NEGATIVE DISEASEb


(category 1)r


(category 1)r



BINV-8

ER-negativeandPR-negativeandHER2

negative


l

��

pT1, pT2, or pT3; pN0

or pN1mi ( 2 mm axillary

node metastasis)

and

�

b .


l

r









Tumor > 1 cm

�

�

Tumor 0.5 cm or

Microinvasive

�

Tumor 0.6-1.0 cm

pN0

pN1mi Consider chemotherapyr

No adjuvant therapy

Consider chemotherapy

(category 1)r




Guidelines Index

Breast Cancer TOC


Histology :TubularColloid

t

��

SYSTEMIC ADJUVANT TREATMENT - FAVORABLE HISTOLOGIES



BINV-9

See Adjuvant Hormonal Therapy (BINV-G)Adjuvant Chemotherapy (BINV-H)

and

n

q




o

p

r

t



�


See text paragraph for medullary carcinoma (MS-21).


metastasis > 2 mm to one or more


< 1 cm

1-2.9 cm

� 3 cm


Consider adjuvant hormonal therapy

+ adjuvant chemotherapy

p

o,q,r

pT1, pT2, or pT3;

pN0 or pN1mi

( 2 mm axillary

node metastasis)

and

�

Adjuvant hormonal therapy +

adjuvant chemotherapy

p

o,q,r

Adjuvant hormonal therapy +

adjuvant chemotherapy

p

o,q,r

ER-positiveand/orPR-positive

ER-negativeandPR-negative

No adjuvant therapy

Adjuvant chemotherapyr




1-2.9 cm

� 3 cm

pT1, pT2, or pT3;

pN0 or pN1mi

( 2 mm axillary

node metastasis)

and

�

< 1 cm

Consider adjuvant chemotherapyr





Guidelines Index

Breast Cancer TOC





See PrimaryTreatment(BINV-11)


b

c.See Principles of HER2 Testing (BINV-A


)

).

Stage IIA

T2, N0, M0

Stage IIB

T2, N1, M0

T3, N0, M0

Stage lllAT3, N1, M0

and

Fulfills criteria for breast

conserving surgery

except for tumor size

��

�

H&PCBC, plateletsLiver function testsChest imagingDiagnostic bilateral mammogram, ultrasound as necessaryPathology reviewDetermination of tumor ER/PR status and HER2 statusBreast MRI (optional)Bone scan (optional) (indicated if localized symptoms or elevated alkalinephosphatase or if T3, N1, M0) (category 2B)Abdominal CT or US or MRI (optional for stage llA or llB, indicated if elevatedalkaline phosphatase, abnormal LFTs, abdominal symptoms, abnormalphysical examination of the abdomen, or if T3, N1, M0) (category 2B)

b

c

BINV-10





Guidelines Index

Breast Cancer TOC




Desiresbreastpreservation

Does not desire

breast preservation

PRIMARY TREATMENT

Core biopsy of

breast tumor,

consider FNA of

clinically positive

axillary lymph

node(s) or sentinel

lymph node

procedure if

clinically negative

axillary lymph

node(s)d

See Stage I and II breast cancer (BINV-1 BINV-2)and

Preoperative

chemotherapy

(Hormonal therapy

alone may be

considered for

receptor positive

disease in

postmenopausal

patients)

u,v

w

Partial

response,

lumpectomy

possiblenot

Partial

response,

lumpectomy

possible

or

Complete

response

No responseafter 3-4cyclesorProgressivediseaseu

d

u Anumber of combination and single agent chemotherapy regimens have activity in the preoperative setting. In general, those chemotherapy regimens recommended inthe adjuvant setting ( ) may be considered in the preoperative setting. If treated with hormonal therapy, an aromatase inhibitor is preferred forpostmenopausal women.

Patients with HER2 positive tumors should be considered for preoperative chemotherapy incorporating trastuzumab .

.

v

w

See Surgical Axillary Staging (BINV-C).

See BINV-H

(See BINV-H)

Definition of Menopause (See BINV-I)

Localizationof tumor bedfor futuresurgicalmanagement

See Lumpectomy Pathway(BINV-12)

BINV-11

Consider

alternative

chemotherapyPartial

response,

lumpectomy

possiblenot

No responseafter 3-4cyclesorProgressivediseaseu

See Mastectomy

Pathway (BINV-12)






Guidelines Index

Breast Cancer TOC


Mastectomy and surgical

axillary staging ±

reconstruction. If

sentinel lymph node

biopsy performed

prechemotherapy and

negative findings, may

omit axillary lymph node

dissection

x

Lumpectomy with

surgical axillary staging.x

If sentinel lymph node

biopsy performed

prechemotherapy and

negative findings, may

omit axillary lymph node

dissection

�

�

Adjuvant RT post-mastectomy is based onprechemotherapy tumor characteristics as per

andHormonal therapy if ER-positive (category 1)

y

p,q

BINV-3

See Adjuvant Hormonal Therapy (BINV-G)

�

�

Adjuvant RT post-lumpectomy based onprechemotherapy tumor characteristics as per

andHormonal therapy if ER-positive (category 1)

y

p,q

BINV-2

See Adjuvant Hormonal Therapy (BINV-G)

See Surveillance/Follow-up (BINV-15)

Consider additional

chemotherapy

LOCAL TREATMENT ADJUVANT TREATMENT



Consider additional

chemotherapy

p

qChemotherapy and hormonal therapy used as adjuvant therapy should be given sequentially with hormonal therapy following chemotherapy. The benefits ofchemotherapy and of hormonal therapy are additive. However, the absolute benefit from chemotherapy may be small. The decision to add chemotherapy to hormonal


Axillary staging may include sentinel node biopsy (category 3) or level l/ll dissection.

�

x

yWhole breast irradiation with boost (by photons, brachytherapy or electron beam) to tumor bed. Boost to tumor bed is especially encouraged in those 50 y of age oryounger. If internal mammary lymph nodes are clinically or pathologically positive, RT should be given to the internal mammary nodes, otherwise the treatment to theinternal mammary nodes is at the discretion of the treating radiation oncologist. CT treatment planning should be utilized in all cases where RT is delivered to theinternal mammary lymph node field.


BINV-12






Guidelines Index

Breast Cancer TOC




��

��

H&PCBC, plateletsLiver function testsChest imagingPathology reviewPrechemotherapy determination of tumor ER/PR receptor statusand HER2Diagnostic bilateral mammogram, ultrasound as necessaryBone scan (category 2B)Abdominal CT or US or MRI (category 2B)Breast MRI (optional)

statusb

c

See Initial Workup for Stage IV Disease (BINV-15)Stage IVAny T, any N, M1


See PreoperativeChemotherapy andLocoregional Treatment(BINV-14)

Stage IIIB

T4, N0, M0

T4, N1, M0

T4, N2, M0

Stage lllC

Any T, N3, M0

Stage IIIA

T0, N2, M0

T1, N2, M0

T2, N2, M0

T3, N2, M0

LOCALLY ADVANCED INVASIVE BREAST CANCER

(Stage IIIA patients with T3,N1, M0 disease, see BINV-1)

BINV-13

b

cSee Principles of HER2 Testing (BINV-A


).

).





Guidelines Index

Breast Cancer TOC


No response

Total mastectomy + surgical axillarystaging + RT to chest wall andsupraclavicular nodes (plus internalmammary nodes if involved) ±delayed breast reconstructionorConsider lumpectomy + surgicalaxillary staging + RT to breast andsupraclavicular nodes (plus internalmammary nodes if involved)z

LOCOREGIONAL TREATMENT

Response

ADJUVANT TREATMENT

Additional chemotherapy +hormonal therapy if estrogenreceptor positive

Consider additional systemicchemotherapy and/or preoperativeradiation

SeeFollow-up/Surveillance(BINV-15)



Response - See above pathway

No responseIndividualizedtreatment

Doxorubicin- orepirubicin-based orpaclitaxel- or docetaxel-based preoperativechemotherapypreferredu,v

PREOPERATIVE CHEMOTHERAPYFOR LOCALLY ADVANCEDINVASIVE BREAST CANCER

BINV-14

uAnumber of combination and single agent chemotherapy regimens have activity in the preoperative setting. In general, those chemotherapy regimens recommendedin the adjuvant setting ( ) may be considered in the preoperative setting. If treated with hormonal therapy, an aromatase inhibitor is preferred forpostmenopausal women.

Patients with HER2 positive tumors should be considered for preoperative chemotherapy incorporating trastuzumabv

zThere are no data regarding breast conserving surgery in the management of inflammatory breast cancer.

See BINV-H

See BINV-H).(





Guidelines Index

Breast Cancer TOC


RECURRENCE WORKUPor

INITIAL WORKUP FOR STAGE IV DISEASE

SURVEILLANCE/FOLLOW-UP

Local

disease only

Systemicdiseaseaa,bb

�

�

�

�

�

Interval history and physical exam every 4-6 mo

for 5 y, then every 12 mo

Mammogram every 12 mo (and 6-12 mo post-RT

if breast conserved) (category 2B)

Women on tamoxifen: annual gynecologic

assessment every 12 mo if uterus present

Women on an aromatase inhibitor or who

experience ovarian failure secondary to

treatment should have monitoring of bone health

Assess and encourage adherence to adjuvant

hormonal therapy.

��

��

�

�

H&PCBC, plateletsLiver function testsChest imagingBone scanX-rays of symptomatic bones and longand weight-bearing bones abnormal onbone scanConsider abdominal CT or MRIBiopsy documentation of firstrecurrence, if possibleConsider determination of tumor ER/PRand HER2 status if unknown, originallynegative or not over-expressedPET scan (optional)(category 2B)

b

See Treatmentof Recurrence/Stage IV Disease(BINV-16)



b

aaPamidronate or zoledronic acid (with calcium citrate 500 mg and vitamin D 400 IU supplement) should be given (category 1) in addition to chemotherapy or

hormonal therapy if bone metastasis present, expected survival 3 months, and creatinine < 3.0 mg/dL.

.

�bb

See Principles of HER2 Testing (BINV-A).

See NCCN Palliative Care Guidelines

BINV-15





Guidelines Index

Breast Cancer TOC


See(BINV-17)

Local

recurrence

Systemic

diseaseaa,bb

TREATMENT OF RECURRENCE/STAGE IV DISEASE

Mastectomy

Consider systemic therapy

Consider systemic therapy

Premenopausalw

Postmenopausalw

HER2 positiveb

HER2 negativeb

Second-line hormonal therapycc

Trastuzumab ± chemotherapydd,ee,ff,gg

Chemotherapydd

No response to 3sequential regimens orECOG performancestatus 3�

Consider nofurther cytotoxictherapybb



b

w .aa

cc

dd

ee

ff

gg

Pamidronate or zoledronic acid (with calcium citrate 500 mg and vitamin D 400 IU supplement) should be given

(category 1) in addition to chemotherapy or hormonal therapy if bone metastasis present, expected survival 3mo, and creatinine < 3.0 mg/dL.

The value of continued trastuzumab following progression on first line-trastuzumab containing chemotherapy formetastatic breast cancer is unknown. The optimal duration of trastuzumab in patients with long-term control ofdisease is unknown.

Trastuzumab given in combination with an anthracycline is associated with significant cardiac toxicity.

Lapatinib plus capecitabine is an option in patients previously treated with an anthracycline, taxane, andtrastuzumab.

�

bb

See Principles of HER2 Testing (BINV-A

Definition of Menopause (See BINV-I)

).

See NCCN Palliative Care Guidelines.

See Subsequent Hormonal Therapy (BINV-J).

See Preferred Chemotherapy Regimens for Recurrent or Metastatic Breast Cancer (BINV-K).

Aromatase inhibitororAntiestrogen

Initial treatment with mastectomy

Initial treatment with lumpectomy + RT

ER/PR positive or

bone/soft tissue only or

asymptomatic visceral

ER/PR negative or

symptomatic visceral

or hormone refractory

Prior antiestrogen

within 1 y

No prior antiestrogen or

> 1 y off antiestrogen

Surgical resection (if possible)

+ RT (if possible)

BINV-16

Ovarian ablation or suppression,

plus hormonal therapy as for

postmenopausal women

orAntiestrogen

TREATMENT OF RECURRENCE

Surgery, radiation ± hyperthermia (category 3 for hyperthermia),

or regional chemotherapy (e.g., intrathecal methotrexate)

indicated for localized clinical scenarios:

1. Brain metastases

2. Leptomeningeal disease

3. Choroid metastases

4. Pleural effusion

5. Pericardial effusion

6. Biliary obstruction

7. Ureteral obstruction

8. Impending pathologic fracture

9. Pathologic fracture

10. Cord compression

11. Localized painful bone or

soft-tissue disease

12. Chest wall disease





Guidelines Index

Breast Cancer TOC




FOLLOW-UP THERAPY FOR HORMONE TREATMENT OF RECURRENCE/STAGE IV DISEASE

cc

dd

hh.

Consideration may be given to further hormone therapy in patients failing to respond to first-line hormone therapy and whose disease is indolent, and for thosepatients achieving a response to chemotherapy and in whom the decision is made to discontinue chemotherapy.

See Subsequent Hormonal Therapy (BINV-J).

See Preferred Chemotherapy Regimens for Recurrent or Metastatic Breast Cancer (BINV-K)

BINV-17

No response tohormonaltherapyhh

Continue hormonaltherapy untilprogression orunacceptable toxicity

No clinical benefit after 3consecutive hormonaltherapy regimensorSymptomatic visceraldisease

Chemotherapydd

(As in BINV-16)

Chemotherapydd

(As in BINV-16)

Yes

NoTrial of newhormone therapy cc

Progression





Guidelines Index

Breast Cancer TOC




BINV-A

PRINCIPLES OF HER2 TESTING1,2

Initial testing

by IHC3

Laboratory meets

quality assurance

standards for IHC

HER2 testing

methodology Yes

No

IHC

testing

IHC 0,1+

IHC 2+

IHC 3+

HER2 (-)

Borderline

result4 FISH testing

HER2 (+)

Send sample to reference laboratory

Yes

No

FISH retest

FISH (-)

FISH+

HER2 (-)

Borderline

result5

HER2 (+)

Send sample to reference laboratory

IHC testing

Count

additional cellsBorderline result

HER2 (-)FISH

testing

Initial testing

by FISH3

Laboratory meets

quality assurance

standards for FISH

HER2 testing

methodology

1

2

5

See also, Carlson RW, Moench SJ, Hammond, MEH, et al. HER2 testing in breast cancer: NCCN task force report and recommendations. JNCCN 4:S-1-S-24, 2006.

a

HER2 testing should be done only in laboratories accredited to perform such testing. Ongoing proficiency testing and full reporting of HER2 assay methods and resultsare required. A laboratory may perform only those tests which have been demonstrated to conform to these quality assurance standards. All other HER2 testing shouldbe sent to a qualified reference laboratory.

3Eithe an immunohistochemistry (IHC) assay or a fluorescence in situ hybridization (FISH) assay can be used to make an initial assessment of HER2 tumor status. AllHER2 assays, whether FDA-approved or not, mu be validated. Validation of a HER2 test is defined as at least 95% concordance when the testing method performedin a laboratory is compared with one of the following: a validated HER2 testing method performed in the same laboratory; a validated HER2 testing method performedin another laboratory; or validated reference lab results. Borderline samples should not be included in the validation study. A validated FDA-approved version of theFISH assay is recommended as the "gold standard" for confirmatory testing, when necessary. These algorithms are based on the assumption that all validated HER2tests have been shown to be at least 95% concordant with the complementary form of the HER2 test, either by direct testing or association with the levels ofconcordance between complementary testing achieved by the validating laboratory.

Borderline IHC samples (eg, IHC 2+) are subjected to reflex testing by a validated complementary (eg, FISH) method that has shown at least 95% concordancebetween IHC 0, 1+ results and FISH non-amplified results, and IHC 3+ results and FISH amplified results for 50-100 samples (where at least half of the casesrepresent HER2 positive tumors).

Borderline FISH samples (eg, an average HER2 gene/chromosome 17 ratio of 1.8-2.2 or an average HER2 gene copy number of > 4 - < 6) should undergo: counting ofadditional cells; retesting by FISH; or reflex testing by a valid ted IHC method which is at least 95% concordant with FISH as described above.

rst

4





Guidelines Index

Breast Cancer TOC




BINV-B

PRINCIPLES OF DEDICATED BREAST MRI TESTING

Personnel, facility and equipment

Breast MRI examinations should be performed and interpreted by an expert breast imaging team working in concert with the

multidisciplinary treatment team.

Breast MRI examinations require a dedicated breast coil and breast imaging radiologists familiar with the optimal timing sequences and

other technical details for image interpretation. The imaging center should have the ability to perform MRI guided needle sampling

and/or wire localization of MRI detected findings.

Clinical indications and applications

Breast MRI examination is an adjunct to other breast imaging and should not be used in lieu of standard breast imaging with

mammography and ultrasound.

For patients with biopsy proven adenocarcinoma presenting in the axilla, a normal clinical breast exam and negative mammogram

(TxN1-3), breast MRI examination is indicated to attempt to identify a primary cancer in the breast.

Breast MRI may be considered for a patient with biopsy-proven breast cancer, when dense breast tissue precludes assessment for

extent of disease.

Breast MRI may be useful in defining the extent of cancer, the presence of multicentric cancer in women with dense breast tissue on

mammography, and extent of disease in women with locally advanced breast cancer. Decision making regarding the extent of breast

surgery (e.g. breast conservation therapy vs. mastectomy) should not be made solely on the basis of MRI and may require additional

tissue sampling of areas of concern identified by breast MRI.

�

�

�

�

�

�





Guidelines Index

Breast Cancer TOC


SURGICAL AXILLARY STAGING - STAGE I, IIA, AND IIB

ClinicalStage I/II

No

Yes

Refer to experienced

sentinel node teamorAxillary dissection level I/II

1,5

Sentinel nodemapping andexcision(preferred)

or

3,4,5

Clinically node

positive at time

of diagnosis2

Clinically node

negative at time

of diagnosis

Sentinel nodenegative6 No further surgery

Sentinel nodepositive6

Sentinel nodenot identified

1

2

3

4

6

Sentinel node team must have documented experience with sentinel node biopsy in breast cancer. Team includes surgeon, radiologists,nuclear medicine physician, pathologist, and prior discussion with medical and radiation oncologists on use of sentinel node fortreatment decisions.

Consider pathologic confirmation of malignancy in clinically positive nodes using ultrasound guided FNA or core biopsy in determiningif patient needs axillary lymph node dissection.

Axillary sentinel node biopsy in all cases; internal mammary sentinel node biopsy optional if drainage maps to internal mammarynodes (category 3).

Sentinel lymph node mapping injections may be peritumoral, subareolar or subdermal. However, only peritumoral injections map to theinternal mammary lymph node(s).

Results of randomized clinical trials indicate that there is a lower risk of mobidity associated with sentinel node mapping and excisionthan with level l/ll axillary dissection.

Sentinel node involvement defined by multilevel node sectioning with hematoxylin and eosin staining. Cytokeratin Immunohistochemistry(IH ) may be used for equivocal cases on H&E. Routine cytokeratin IHC to define node involvement is controversial (category 3).

5

C

Sentinel lymph nodecandidate - Meeting ALLof the following criteria:

No prior chemotherapyor hormonal therapy

AND

Experienced sentinelnode team

�

1



Return toLocoregionalTreatment(BINV-2)

BINV-C

FNA or core

biopsy negative

Axillary dissectionlevel I/II

Axillary dissection level I/II

Axillary dissection level I/II





Guidelines Index

Breast Cancer TOC


In the absence of definitive data demonstrating superior survival from the performance of axillary lymph nodedissection, patients who have particularly favorable tumors, patients for whom the selection of adjuvantsystemic therapy is unlikely to be affected, for the elderly, or those with serious comorbid conditions, theperformance of axillary lymph node dissection may be considered optional. The axillary dissection should beextended to include level lll nodes only if there is gross disease apparent in the level ll nodes.

Sentinel lymph node biopsy is the preferred method of axillary lymph node staging if there is an experiencedsentinel node team and the patient is an appropriate sentinel lymph node biopsy candidate (See BINV-C).

AXILLARY LYMPH NODE STAGING



BINV-D





Guidelines Index

Breast Cancer TOC




BINV-E

MARGIN STATUS IN INFILTRATING CARCINOMA

The use of breast conserving therapy is predicated on achieving a pathologically negative margin of resection.Cases where there is a positive margin should undergo further surgery, either a re-excision to achieve a negativemargin or a mastectomy. If re-excision is technically feasible to allow for breast conserving therapy, this can be donewith resection of the involved margin guided by the orientation of the initial resection specimen or re-excision of theentire original excision cavity. If multiple margins remain positive, mastectomy may be required for optimal localcontrol.

It may be reasonable to treat selected cases with breast conserving therapy with a microscopically focally positivemargin in the absence of an extensive intraductal component. For these patients, the use of a higher radiationboost dose to the tumor bed should be considered.

Margins should be evaluated on all surgical specimens from breast conserving surgery. Requirements for optimalmargin evaluation include:

Orientation of the surgical specimens

Description of the gross and microscopic margin status

Reporting of the distance, orientation, and type of tumor (invasive or DCIS) in relation to the closest margin.

1

�

�

�

1An extensive intraductal component is defined as an infiltrating ductal cancer where greater than 25% of the tumor volume is DCIS andDCIS extends beyond the invasive cancer into surrounding normal breast parenchyma.





Guidelines Index

Breast Cancer TOC


SPECIAL CONSIDERATIONS TO BREAST-CONSERVING THERAPY REQUIRING RADIATION THERAPY



Contraindications for breast-conserving therapy requiring radiation therapy include:

Absolute:

Relative:

�

�

�

�

�

�

�

�

�

Prior RT to the breast or chest wall

RT during pregnancy

Diffuse suspicious or malignant appearing microcalcifications

Widespread disease that cannot be incorporated by local excision through a single incision that

achieves negative margins with a satisfactory cosmetic result.

Positive pathologic margin

Active connective tissue disease involving the skin (especially scleroderma and lupus)

Tumors > 5 cm (category 2B)

Focally positive margin

Have an increased risk of ipsilateral breast recurrence or contralateral breast cancer with

breast conserving therapyProphylactic bilateral mastectomy for risk reduction may be considered.

1

1

Women 35 y or premenopausal women with a known BRCA 1/2 mutation:��

�

( ).See NCCN Breast Cancer Risk Reduction Guidelines

BINV-F

1See Margin Status in Infiltrating Carcinoma (BINV-E).





Guidelines Index

Breast Cancer TOC




ADJUVANT HORMONAL THERAPY

BINV-G

Adjuvant

hormonal

therapy

Premenopausal1

Postmenopausal1

Tamoxifen for 2-3 y

(category 1) ± ovarian

suppression or

ablation (category 2B)

2Exemestane or anastrozole to

complete 5 y adjuvant hormonal

therapy (category 2B)3,4

Complete 5 y

tamoxifen

(category 1)

2

Letrozole for 5 y

(category 1)3

No further

hormonal

therapy

1

2Some serotonin reuptake inhibitors decrease the formation of endoxifen, an active metabolite of tamoxifen. However, citalopram and venlafaxine appear to haveminimal impact on tamoxifen metabolism. The clinical impact of these observations is not known.

3

4

The panel believes the three selective aromatase inhibitors (anastrozole, letrozole, exemestane) have similar antitumor efficacy and similar toxicity profiles. Thearomatase inhibitor(s) specified is that used in the clinical trial(s) that most closely approximates the clinical situation. The optimal duration of aromatase inhibitors inadjuvant therapy is uncertain.

This specific patient subset was not included in the trials of aromatase inhibitors given sequentially with adjuvant tamoxifen. Some women who appear to becomepostmenopausal on tamoxifen therapy have resumption of ovarian function after discontinuation of tamoxifen and initiation of an aromatase inhibitor. Therefore, serialmonitoring of plasma estradiol and FSH levels is encouraged in this clinical setting. Should ovarian function resume, the aromatase inhibitor should be discontinued andtamoxifen resumed.

See Definition of Menopause (BINV-I)

See Definition of Menopause (BINV-I)

.

.

Anastrozole or letrozole for 5 y (category 1)3

Tamoxifen for 2-3 y2

Tamoxifen to 4.5-6 y2

Women with contra-indication to aromatase inhibitors,

who decline aromatase inhibitors or who are intolerant of

the aromatase inhibitors, tamoxifen for 5 y (category 1)2

Letrozole for 5 y (category 1)3

Exemestane or anastrozole to

complete 5 y adjuvant

hormonal therapy (category 1)3

Postmenopausal1

Premenopausal1

Postmenopausal1

Premenopausal1

Complete 5 y tamoxifen

(category 1)

2 Letrozole for 5 y

(category 1)3





Guidelines Index

Breast Cancer TOC


ADJUVANT CHEMOTHERAPY 1,2,3,4,5

1

2

3

4

5

6

7

8

Retrospective evidence suggests that anthracycline-based chemotherapy regimens may be superior to non-anthracycline-based regimens in patients with HER2positive tumors.

CMF and radiation therapy may be given concurrently, or the CMF may be given first. All other chemotherapy regimens should be given prior to radiotherapy.

Chemotherapy and tamoxifen used as adjuvant therapy should be given sequentially with tamoxifen following chemotherapy.

For node-positive patients, anthracycline-containing chemotherapy regimens are preferred.

Randomized clinical trials demonstrate that the addition of a taxane to anthracycline-based chemotherapy provides an improved outcome.

The data supporting A CMF are limited to patients with four or more positive nodes.

A single randomized clinical trial with 36 mo median follow-up demonstrated superior disease-free and overall survival with every two weekly treatment with AC x 4sequential with paclitaxel x 4 or with A x 4 followed by T x 4, followed by C x 4 versus every 3 weekly treatment with the same regimens.

For specific regimens see Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2 positive breast cancer. N Engl JMed 2005;353:1659-72.

In patients with HER2 positive and axillary lymph node positive breast cancer, trastuzumab should be incorporated into the adjuvant therapy. (category 1) Trastuzumabshould also be considered for patients with lymph node negative tumors greater than or equal to 1 cm and are HER2 positive. (category 1) Trastuzumab may be givenbeginning either concurrent with paclitaxel as part of the AC followed by paclitaxel regimen, or alternatively after the completion of chemotherapy. Trastuzumab shouldnot be given concurrent with an anthracycline because of cardiac toxicity. Trastuzumab should be given for one year, (with the exception of the docetaxel +trastuzumab FEC regimen in which trastuzumab was given for 9 weeks), with cardiac monitoring, and by either the weekly or every three weekly schedule.

9



�

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�

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FAC/CAF (fluorouracil/doxorubicin/cyclophosphamide) or

FEC/CEF (cyclophosphamide/epirubicin/fluorouracil)AC (doxorubicin/cyclophosphamide) ± sequential paclitaxelEC (epirubicin/cyclophosphamide)TAC (docetaxel/doxorubicin/cyclophosphamide)A CMF (doxorubicin followed by cyclophosphamide/

methotrexate/fluorouracil)E CMF (epirubicin followed by

cyclophosphamide/methotrexate/fluorouracil)CMF (cyclophosphamide/methotrexate/fluorouracil)AC x 4 (doxorubicin/cyclophosphamide) + sequential paclitaxel x 4,

every 2 weekly regimen with filgrastim supportA T C (doxorubicin followed by paclitaxel followed by

cyclophosphamide) every 2 weekly regimen with filgrastim support

6

6

7

8

8

with filgrastim support

FEC T (fluorouracil/epirubicin/cyclophosphamide followed by

docetaxel)

See Representative Adjuvant Chemotherapy Regimens on next page, BINV-H (2 of 5)

BINV-H1 of 5

NON-TRASTUZUMAB CONTAINING REGIMENS all( category 1) TRASTUZUMAB CONTAINING REGIMENS all( category 1)

Preferred Adjuvant Regimen:

Other Adjuvant Regimens:

Docetaxel + trastuzumab FEC

TCH (docetaxel, carboplatin, trastuzumab)

Chemotherapy followed by trastuzmab sequentially

AC docetaxel + trastuzumabNeoadjuvant:

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AC T + concurrent trastuzumab

(doxorubicin/cyclophosphamide followed by paclitaxel plus

trastuzumab)

T + trastuzumab CEF + trastuzumab

(paclitaxel plus trastuzumab followed by

cyclophosphamide/epirubicin/fluorouracil plus trastuzumab)

9





Guidelines Index

Breast Cancer TOC


FAC chemotherapy

5-Fluorouracil 500 mg/m IV days 1 & 8 ordays 1 & 4

Doxorubicin 50 mg/m IV day 1(or by 72 h continuous infusion)

Cyclophosphamide 500 mg/m IV day 1Cycled every 21 days for 6 cycles.

CAF chemotherapy

Cyclophosphamide 100 mg/m PO days 1-14

Doxorubicin 30 mg/m IV days 1 & 8

5-Fluorouracil 500 mg/m IV days 1 & 8Cycled every 28 days for 6 cycles.

AC chemotherapy

Doxorubicin 60 mg/m IV day 1


1,2

2

3

5

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�

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�

�

�

�

�

2

2

2

2

2

4

2

2

2

2

2

FEC chemotherapy


Epirubicin 60 mg/m IV days 1 & 8

5-Fluorouracil 500 mg/m IV days 1 & 8With cotrimoxazole support.Cycled every 28 days for 6 cycles.

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REPRESENTATIVE ADJUVANT CHEMOTHERAPY REGIMENS FOR BREAST CANCER*

NON-TRASTUZUMAB COMBINATIONS

*The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and scheduleand initiation of supportive care interventions are often necessary because of expected toxicities and because of individual patient variability, prior treatment, andcomorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and themanagement of associated toxicities in patients with cancer.



AC followed by paclitaxel chemotherapy


Cyclophosphamide 600 mg/m IV day 1Cycled every 21 days for 4 cycles.Followed by

Paclitaxel 175-225 mg/m by 3 h IV infusion day 1Cycled every 21 days for 4 cycles.OR

Paclitaxel 80 mg/m by 1 h IV infusion

weekly for 12 weeks.

EC chemotherapy

Epirubicin 100 mg/m IV day 1


TAC chemotherapy

Docetaxel 75 mg/m IV day 1


Cyclophosphamide 500 mg/m IV day 1Cycled every 21 days for 6 cycles.(All cycles are with filgrastim support).

A followed by CMF chemotherapy

Doxorubicin 75 mg/m IV day 1Cycled every 21 days for 4 cycles.Followed by

Cyclophosphamide 600 mg/m IV day 1

Methotrexate 40 mg/m IV day 1

5-Fluorouracil 600 mg/m IV day 1Cycled every 21 days for 8 cycles.

6,7

2

2

2

2

8

2

2

9

2

2

2

10

2

2

2

2

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E followed by CMF chemotherapy

Epirubicin 100 mg/m IV day 1Cycled every 21 days for 4 cycles.Followed by


Methotrexate 40 mg/m IV days 1 & 8

5-Fluorouracil 600 mg/m IV days 1 & 8Cycled every 28 days for 4 cycles.OR

Cyclophosphamide 750 mg/m IV day 1

Methotrexate 50 mg/m IV day 1

5-Fluorouracil 600 mg/m IV day 1Cycled every 21 days for 4 cycles.

CMF chemotherapy



5-Fluorouracil 600 mg/m IV days 1 & 8Cycled every 28 days for 6 cycles.

Dose-dense AC followed by paclitaxelchemotherapy



Paclitaxel 175 mg/m by 3 h IV infusion day 1Cycled every 14 days for 4 cycles.(All cycles are with filgrastim support).

11

2

2

2

2

2

2

2

12

2

2

2

13

2

2

2

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BINV-H2 of 5





Guidelines Index

Breast Cancer TOC




*The selection, dosing, and administration of anti-cancer agents and the management of associatedtoxicities are complex. Modifications of drug dose and schedule and initiation of supportive careinterventions are often necessary because of expected toxicities and because of individual patientvariability, prior treatment, and comorbidity. The optimal delivery of anti-cancer agents thereforerequires a health care delivery team experienced in the use of anti-cancer agents and themanagement of associated toxicities in patients with cancer.

BINV-H3 of 5

TRASTUZUMAB CONTAINING COMBINATIONS

AC followed by T chemotherapy with

Trastuzumab



Paclitaxel 175 mg/m by 3 h IV day 1Cycled every 21 days for 4 cyclesOR

Paclitaxel 80 mg/m by 1 h IV weekly for 12 wksWith

Trastuzumab 4 mg/kg IV with first dose of

paclitaxelFollowed by

Trastuzumab 2 mg/kg IV weekly to complete 1 y

of treatment. As an alternative, trastuzumab 6

mg/kg IV every 3 wk may be used following the

completion of paclitaxel, and given to complete

1y of trastuzumab treatment.Cardiac monitoring at baseline, 3, 6, and 9 mo.

15

2

2

2

2

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Dose-dense A-T-C chemotherapy

Doxorubicin 60 mg/m IV day 1Cycled every 14 days for 4 cycles.Followed by

Paclitaxel 175 mg/m by 3 h IV day 1Cycled every 14 days for 4 cycles.Followed by

Cyclophosphamide 600 mg/m IV day 1Cycled every 14 days for 4 cycles.(All cycles are with filgrastim support).

FEC followed by docetaxelchemotherapy

5-Fluorouracil 500 mg/m IV day 1

Epirubicin 100 mg/m IV day 1

Cyclophosphamide 500 mg/m day 1Cycled every 21 days for 3 cycles.Followed by

Docetaxel 100 mg/m day 1Cycled every 21 days for 3 cycles.

13

2

2

2

14

2

2

2

2

�

�

�

�

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Docetaxel + trastuzumab followed by FEC

Docetaxel 100 mg/m by 1 h IV day 1Cycled every 21 days for 3 cyclesWith

Trastuzumab 4 mg/kg IV with first dose of

docetaxel day 1Followed by

Trastuzumab 2 mg/kg IV weekly to complete 9

weeks of trastuzumab.Followed by

5-Fluorouracil 600 mg/m IV day 1

Epirubicin 60 mg/m day 1

Cyclophosphamide 600 mg/m day 1Cycled every 21 days for 3 cyclesCardiac monitoring at baseline, after last FEC

cycle, at 12 and 36 mo after chemotherapy.

TCH (docetaxel, carboplatin, trastuzumab)


16

2

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2

2

17

2

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Followed by

Carboplatin AUC 6 IV day 1Cycled every 21 days for 6 cyclesWith

Trastuzumab 4 mg/kg week 1Followed by

Trastuzumab 2 mg/kg for 17 weeksFollowed by

Trastuzumab 6 mg/kg IV every 3 weeks to

complete 1 year of trastuzumab therapyCardiac monitoring at baseline, 3, 6, and 9 mo.


NON-TRASTUZUMAB COMBINATIONS





Guidelines Index

Breast Cancer TOC


*The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule andinitiation of supportive care interventions are often necessary because of expected toxicities and because of individual patient variability, prior treatment, andcomorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and themanagement of associated toxicities in patients with cancer.

Neoadjuvant T followed by FEC

chemotherapy with trastuzumab

Trastuzumab 4 mg/kg IV for one dose

beginning just prior to first dose of

paclitaxelFollowed by

Trastuzumab 2 mg/kg IV weekly for 23 wks

Paclitaxel 225 mg/m by 24 h IV infusion

every 21 days for 4 cyclesFollowed by

5-Fluorouracil 500 mg/m on days 1 and 4

Epirubicin 75 mg/m IV on day 1

Cyclophosphamide 500 mg/m on day 1Cycled every 21 days for 4 cycles.

19

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2

2

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2



BINV-H4 of 5


Chemotherapy followed by trastuzumab

Approved adjuvant chemotherapy regimen for at least 4

cyclesFollowed by

Trastuzumab 8 mg/kg IV times 1 doseFollowed by

Trastuzumab 6 mg/kg IV every 21 days for 1 yCardiac monitoring at baseline, 3, 6, and 9 mo.

AC followed by docetaxel with trastuzumab


Cyclophosphamide 600 mg/m day 1Cycled every 21 days for 4 cyclesFollowed by

Docetaxel 100 mg/mCycled every 21 days for 4 cyclesWith

Trastuzumab 4 mg/kg IV week oneFollowed by

Trastuzumab 2 mg/kg IV weekly for 11 weeksFollowed by

Trastuzumab 6 mg/kg every 21 days to complete 1 y of

trastuzumab therapy

18

17

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2

2

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Cardiac monitoring at baseline, 3, 6, and 9 mo.

TRASTUZUMAB CONTAINING COMBINATIONS





Guidelines Index

Breast Cancer TOC




REFERENCES FOR REPRESENTATIVE ADJUVANT CHEMOTHERAPY REGIMENS FOR BREAST CANCER

1

12

15

Buzdar AU, Kau SW, Smith TL, Hortobagyi GN. Ten-year results of FAC adjuvant chemotherapy trial in breast cancer. Am J Clin Oncol 12; 123-128,

Assikis V, Buzdar A, Yang Y, et al: A phase III trial of sequential adjuvant chemotherapy for operable breast carcinoma: final analysis with 10-year follow-up. Cancer97:2716-23, 2003

Bull JM, Tormey DC, Li SH, et al: A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer 41:1649-57, 1978

Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with six months ofcyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from NSABP B-15. Journal ofClinical Oncology 8:1483-1496, 1990

Piccart MJ, Di Leo A, Beauduin M, et al: Phase III Trial Comparing Two Dose Levels of Epirubicin Combined With Cyclophosphamide With Cyclophosphamide,Methotrexate, and Fluorouracil in Node-Positive Breast Cancer. J Clin Oncol 19:3103-3110, 2001

Results from NSABP B-28. Proc Am Soc Clin Oncol 22:Abstract 12, 2003

Goldhirsch A, Colleoni M, Coates AS, et al: Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: are all CMFs alike? The International BreastCancer Study Group (IBCSG). Ann Oncol 9:489-93, 1998

Roche H, Fumoleau P, Spielmann, et al. Five years analysis of the PACS 01 trial: 6 cycles of FEC 100 vs 3 cycles of FEC 100 followed by 3 cycles of docetaxel (D) forthe adjuvant treatment of node positive breast cancer [abstract]. 2004 San Antonio Breast Cancer Symposium. Abstract 27, General Session 4.

Romond EH, Perez EZ, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2 positive breast cancer. N Engl J Med 353:1673-1684,

Joensuu H, Kellokumpu-Lehtinen P-L, Bono P, et al: Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354:809-20, 2006.

Slamon D, Eirmann W, Robert N, et al. Phase lll randomized trial compaing doxorubicin and cyclophosphamide followed by docetaxel with doxorubicin andtrastuzumab with docetaxel, carboplatin and trastuzumab in HER2 positive early breast cancer patients: BCIRG 006 study (Abstr.#1).San Antonio Breast CancerSymposium 2005.

Buzdar A, Ibrahim N, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicinchemotherapy: Results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J. Clin Oncol 23: 3676-3685,

1989

Levine MN, Bramwell VH, Pritchard KI, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared withcyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical TrialsGroup. J Clin Oncol 16:2651-8, 1998

Henderson IC, Berry DA, Demetri GD, et al: Improved Outcomes From Adding Sequential Paclitaxel but Not From Escalating Doxorubicin Dose in an AdjuvantChemotherapy Regimen for Patients With Node-Positive Primary Breast Cancer. J Clin Oncol 21:976-983, 2003

Mamounas EP, Bryant J, Lembersky BC, et al: Paclitaxel (T) following doxorubicin/cyclophosphamide (AC) as adjuvant chemotherapy for node-positive breast cancer:

Nabholtz J-M, Pienkowski T, Mackey J, et al: Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin,cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: interim analysis of the BCIRG 001 study. Proc Am Soc Clin Oncol21:Abstract 141, 2002

Bonadonna G, Zambetti M, Valagussa P: Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. Ten-yearresults. JAMA 273:542-7, 1995

Poole CJ, Earl HM, Dunn JA, et al: NEAT (National Epirubicin Adjuvant Trial) and SCTBG BR9601 (Scottish Cancer Trials Breast Group) phase III adjuvant breast trialsshow a significant relapse-free and overall survival advantage for sequential ECMF. Proc Am Soc Clin Oncol 22:Abstract 13, 2003

Citron ML, Berry DA, Cirrincione C, et al: Randomized Trial of Dose-Dense Versus Conventionally Scheduled and Sequential Versus Concurrent CombinationChemotherapy as Postoperative Adjuvant Treatment of Node-Positive Primary Breast Cancer: First Report of Intergroup Trial C9741/Cancer and Leukemia Group BTrial 9741. J Clin Oncol 21:1431-1439, 2003

2005

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER-2 positive breast cancer. N Engl J Med 353:1659-72, 2005

2005

2

3

5

8

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16

17

19

4

9

10

11

18

6

7

13

BINV-H5 of 5





Guidelines Index

Breast Cancer TOC




BINV-I

DEFINITION OF MENOPAUSE

Clinical trials in breast cancer have utilized a variety of definitions of menopause. Menopause is generally the

permanent cessation of menses, and as the term is utilized in breast cancer management includes a

profound and permanent decrease in ovarian estrogen synthesis. Reasonable criteria for determining

menopause include any of the following:

Prior bilateral oophorectomy

Age 60 y

Age < 60 y and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene,

or ovarian suppression and FSH and estradiol in the postmenopausal range

If taking tamoxifen or toremifene, and age < 60 y, then FSH and plasma estradiol level in postmenopausal

ranges

It is not possible to assign menopausal status to women who are receiving an LH-RH agonist or antagonist.

In women premenopausal at the beginning of adjuvant chemotherapy, amenorrhea is not a reliable indicator

of menopausal status as ovarian function may still be intact or resume despite anovulation/amenorrhea after

chemotherapy. For these women with therapy-induced amenorrhea, oophorectomy or serial measurement of

FSH and/or estradiol are needed to ensure postmenopausal status if the use of aromatase inhibitors is

considered as a component of endocrine therapy.

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� �

�

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Guidelines Index

Breast Cancer TOC




SUBSEQUENT HORMONAL THERAPY FOR SYSTEMIC DISEASE(For first-line hormonal therapy see BINV-16)

POSTMENOPAUSAL PATIENTS

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�

�

�

�

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Non-steroidal aromatase inhibitor (anastrozole, letrozole)

or steroidal aromatase inactivator (exemestane)

Fulvestrant

Tamoxifen or Toremifene

Megestrol acetate

Fluoxymesterone

Ethinyl estradiol

BINV-J

Premenopausal patients with ER-positive disease should have

ovarian ablation/suppression and follow postmenopausal guideline





Guidelines Index

Breast Cancer TOC


PREFERRED CHEMOTHERAPY REGIMENS FOR RECURRENT OR METASTATIC BREAST CANCER1 (page 1 of 6)



Preferred Single Agents

��

DoxorubicinEpirubicinPegylated liposomal doxorubicinPaclitaxelDocetaxelCapecitabineVinorelbineGemcitabineAlbumin-bound paclitaxel

Preferred Combinations

�

��

CAF/FAC (cyclophosphamide/doxorubicin/fluorouracil)FEC (fluorouracil/epirubicin/cyclophosphamide)AC (doxorubicin/cyclophosphamide)EC (epirubicin/cyclophosphamide)AT (doxorubicin/docetaxel; doxorubicin/paclitaxel)CMF (cyclophosphamide/methotrexate/fluorouracil)Docetaxel/capecitabineGT (gemcitabine/paclitaxel)

Other Active Agents

��

CisplatinCarboplatinEtoposide (po)VinblastineFluorouracil continuous infusion

1There is no compelling evidence that combination regimens are superior to sequential single agents.

A single randomized clinical trial documents superior time to progression and survival with the combination of bevacizumab plus paclitaxel compared with paclitaxelalone for first line chemotherapy of metastatic disease.

2

See Representative Chemotherapy Regimens on next page, BINV-K (2 of 6)

PREFERRED CHEMOTHERAPY REGIMENS FOR USE IN COMBINATION WITH TRASTUZUMAB(HER2 positive metastatic disease)

Paclitaxel ± CarboplatinDocetaxelVinorelbine

BINV-K1 of 6

Preferred Agents with Bevacizumab

� Paclitaxel2





Guidelines Index

Breast Cancer TOC


(Page 2 of 6)



REPRESENTATIVE CHEMOTHERAPY REGIMENS FOR METASTATIC BREAST CANCER*


CAF chemotherapy


Doxorubicin 30 mg/m IV days 1 & 8

5-Fluorouracil 500 mg/m IV days 1 & 8Cycled every 28 days.

FAC chemotherapy

5-Fluorouracil 500 mg/m IV days 1 & 8 or days 1 & 4


Cyclophosphamide 500 mg/m IV day 1Cycled every 21 days.

AC chemotherapy


Cyclophosphamide 600 mg/m IV day 1Cycled every 21 days.

CMF chemotherapy




1

2

3

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2

2

2

2

2

2

2

2

2

2

2

4

Docetaxel and Capecitabine


Capecitabine 950 mg/m PO twice daily days 1-14Cycled every 21 days.

GT Chemotherapy

Paclitaxel 175 mg/m IV by 3 h IV infusion day 1

Gemcitabine 1250 mg/m IV days 1 & 8 (following paclitaxel on day 1)Cycled every 21 days.

FEC chemotherapy

Cyclophosphamide 400 mg/m IV days 1 & 8

Epirubicin 50 mg/m IV days 1 & 8


5

2

2

6

2

2

7

2

2

2

�

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COMBINATIONS

Continued on next page, BINV-K (3 of 6)

BINV-K2 of 6





Guidelines Index

Breast Cancer TOC


(Page 3 of 6)

SINGLE AGENTS

�

�

�

�

�

�

�

Doxorubicin 60-75 mg/m IV day 1, cycled every 21 days

OR

Doxorubicin 20 mg/m IV, weekly.

Epirubicin 60-90 mg/m IV day 1Cycled every 21 days.

Pegylated liposomal encapsulated doxorubicin 50 mg/m IV day 1Cycled every 28 days.

Paclitaxel 175 mg/m by 3 h IV infusion day 1Cycled every 21 days.

OR

Paclitaxel 80 mg/m by 1 h IV infusion weekly.

Cycled every 21 days.

OR



Albumin-bound paclitaxel 260 mg/m by 30 minute IV infusionCycled every 21 days.

8

11

13,14

17

2

2

9 2

10 2

12

2

18

2

2

2

2

15

2 16

2

2

�

�

�

�

�

Docetaxel 60-100 mg/m by 1 h IV infusion day 1

Docetaxel 40 mg/m by 1 h IV infusion weekly for 6 wks followed bya 2 week rest, then repeated.

Vinorelbine 25 mg/m IV weekly

Capecitabine 1000-1250 mg/m PO twice daily days 1-14

Gemcitabine 800-1200 mg/m IV days 1, 8 & 15

REPRESENTATIVE CHEMOTHERAPY REGIMENS FOR METASTATIC BREAST CANCER*




Continued on next page, BINV-K (4 of 6)

BINV-K3 of 6

BEVACIZUMAB CONTAINING REGIMENS

Paclitaxel plus bevacizumab

Paclitaxel 90 mg/m by 1 h IV days 1, 8 & 15

Bevacizumab 10 mg/kg IV days 1 & 15Cycled every 28 days.

19

2�

�





Guidelines Index

Breast Cancer TOC


(Page 4 of 6)



REPRESENTATIVE CHEMOTHERAPY REGIMENS FOR METASTATIC BREAST CANCER IN COMBINATION WITH TRASTUZUMAB*

PCH

Carboplatin AUC of 6 IV day 1


Weekly TCH

Paclitaxel 80 mg/m by 1 h IV infusion days 1, 8 & 15

Carboplatin AUC of 2 IV days 1, 8 & 15Cycled every 28 days.


OR

Paclitaxel 80-90 mg/m by 1 h IV infusion weekly

Docetaxel 80 to 100 mg/m by 30 min IV infusion day 1Cycled every 21 days

OR

Docetaxel 35 mg/m by 30 min IV infusion weekly

Vinorelbine 25 mg/m IV weekly

20

21

2

2

23

24

15,25

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�

�

�

�

�

�

�

2

22

SINGLE AGENTS

2

2

2

2

Trastuzumab 4 mg/kg IV by 90 min infusion day 1Followed by2 mg/kg IV by 30 min infusion weeklyORTrastuzumab 8 mg/kg IV by 90 min infusion day 1Followed by6 mg/kg IV by 90 min infusion every 3 weeks

22,26

27

CHEMOTHERAPY COMPONENT TRASTUZUMAB COMPONENT

See References on next page, BINV-K (5 of 6)

COMBINATIONS

BINV-K4 of 6






Guidelines Index

Breast Cancer TOC


See References on next page, BINV-I (6 of 6)

(Page 5 of 6)



REFERENCES FOR REPRESENTATIVE CHEMOTHERAPY REGIMENS FORMETASTATIC BREAST CANCER and in COMBINATION WITH TRASTUZUMAB*

1

2

3

4

5

6

7

8

9

11

12

Bull JM, Tormey DC, Li SH, et al: A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer 41:1649-57, 1978

Hortobagyi GN, Gutterman JU, Blumenschein GR, et al: Combination chemoimmunotherapy of metastatic breast cancer with 5-fluorouracil, adriamycin,cyclophosphamide, and BCG. Cancer 43:1225-33, 1979

Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with six months ofcyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from NSABP B-15. Journalof Clinical Oncology 8:1483-1496, 1990

Bonadonna G, Brusamolino E, Valagussa P, et al: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 294:405-10, 1976

O'Shaughnessy J, Miles D, Vukelja S, et al: Superior Survival With Capecitabine Plus Docetaxel Combination Therapy in Anthracycline-Pretreated Patients WithAdvanced Breast Cancer: Phase III Trial Results. J Clin Oncol 20:2812-2823, 2002

Albain K.S., Nag S., et al: Global Phase lll Study of Gemcitabine Plus Paclitaxel (GT) vs. Paclitaxel (T) as Frontline Therapy for Metastatic Breast Cancer (MBC); FirstReport of Overall Survival. J Clin Oncol 22 No 14S: 510, 2004.

Ackland SP, Anton A, Breitbach GP, et al: Dose-Intensive Epirubicin-Based Chemotherapy Is Superior to an Intensive Intravenous Cyclophosphamide, Methotrexate,and Fluorouracil Regimen in Metastatic Breast Cancer: A Randomized Multinational Study. J Clin Oncol 19:943-953, 2001

Gundersen S, Kvinnsland S, Klepp O, et al: Weekly adriamycin versus VAC in advanced breast cancer. A randomized trial. Eur J Cancer Clin Oncol. 22:1431-4, 1986

Bastholt, L., Dalmark, M., et al: Dose-Response Relationship of Epirubicin in the Treatment of Postmenopausal Patients with Metastatic Breast Cancer: ARandomized Study of Epirubicin at Four Different Dose Levels Performed by the Danish Breast Cancer Coopertive Group.J Clin Oncol 14: 1146-1155, 1996.

O’Brien, M. E., Wigler, N., et al: Reduced Cardiotoxicity and Comparable Efficacy in a Phase lll Trial of Pegylated Liposomal Doxorubicin HC1 (CAELYX/Doxil) vs.Conventional Doxorubicin for First-Line Treatment of Metastatic Breast Cancer. Ann Oncol 15(3): 440-9, 2004

Seidman A, Tiersten A, Hudis C, et al: Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol13:2575-2581, 1995

Perez EA, Vogel CL, Irwin DH, et al: Multicenter Phase II Trial of Weekly Paclitaxel in Women With Metastatic Breast Cancer. J Clin Oncol 19:4216-4223, 2001

10

BINV-K5 of 6





Guidelines Index

Breast Cancer TOC


(Page 6 of 6)

13

14

15

16

17

27

Burris HAR: Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol. 26:1-6, 1999

Valero V: Docetaxel as single-agent therapy in metastatic breast cancer: clinical efficacy. Semin Oncol. 24(Suppl 13):S11-18, 1997

Burstein HJ, Manola J, Younger J, et al: Docetaxel Administered on a Weekly Basis for Metastatic Breast Cancer. J Clin Oncol 18:1212-1219, 2000

Zelekv L, Barthier S, Riofrio M, et al: Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma.Cancer 92:2267-72, 2001

Seidman AD: Gemcitabine as single-agent therapy in the management of advanced breast cancer. Oncology (Huntingt) 15(Suppl 3):11-14, 2001

2005

Esteva FJ, Valero V, Booser D, et al: Phase II Study of Weekly Docetaxel and Trastuzumab for Patients With HER2-Overexpressing Metastatic Breast Cancer. J ClinOncol 20:1800-1808, 2002

Burstein HJ, Kuter I, Campos SM, et al: Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol19:2722-30, 2001

Cobleigh MA, Vogel CL, Tripathy D, et al: Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic Disease. J Clin Oncol 17:2639-48, 1999

Leyland-Jones, Gelman et al: Pharmacokinetics, Safety, and Efficacy of Trastuzumab Administered Every Three Weeks in Combination with Paclitaxel. J Clin Oncol21: 3965-3971, 2003.

18Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III Trial of Nanoparticle Albumin-Bound Paclitaxel Compared With Polyethylated Castor Oil-Based Paclitaxel inWomen With Breast Cancer. J Clin Oncol 23:7794-7803,

Miller KD. E2100: a phase III trial of paclitaxel versus paclitaxel/bevacizumab for metastatic breast cancer.Clin Breast Cancer (United States), Feb 2003, 3(6) p421-219

20

21

22

23

24

25

26

Robert N, Leyland-Jones B, Asmar L, et al: Phase III comparative study of trastuzumab and paclitaxel with and without carboplatin in patients with HER2 positiveadvanced breast cancer. 25th Annual San Antonio Breast Cancer Symposium:Abstract 35, 2002

Perez E.Carboplatin in combination therapy for metastatic breast cancer. The Oncologist 9:518-527, 2004

Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. NEngl J Med 344:783-92, 2001

Seidman AD, Fornier MN, Esteva FJ, et al: Weekly Trastuzumab and Paclitaxel Therapy for Metastatic Breast Cancer With Analysis of Efficacy by HER2Immunophenotype and Gene Amplification. J Clin Oncol 19:2587-2595, 2001

REFERENCES FOR REPRESENTATIVE CHEMOTHERAPY REGIMENS FORMETASTATIC BREAST CANCER and in COMBINATION WITH TRASTUZUMAB*




BINV-K6 of 6




Guidelines Index

Breast Cancer TOC


CLINICAL PRESENTATION

Clinical suspicion of phyllodes

tumor:

Palpable mass

Rapid growth

Large size (> 2 cm)

Imaging with ultrasound

suggestive of fibroadenoma except

for size and/or history of growth

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History and

physical exam

Ultrasound

Mammogram for

women 30 y

Excisional

biopsyb

Core needle

biopsya

Fibroadenoma

or indeterminate

Fibroadenoma

Phyllodes

tumor

Observe

Wide excision

without axillary staging

c

Excisional

biopsyb Observe



a

b

c

FNA will not, and core biopsy may not distinguish fibroadenoma from phyllodes tumor in most cases.

Excisional biopsy includes complete mass removal, but without the intent of obtaining surgical margins.

Wide excision means exision with the intention of obtaining surgical margins 1 cm. Narrow surgical margins are associated with heightened local recurrence

risk, but are not an absolute indication for mastectomy when partial mastectomy fails to achieve margin width 1 cm.

�

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WORKUP FINDINGS TREATMENT

Invasive or

in situ cancer

See appropriate

guideline

Phyllodes

tumor

Wide excision

without axillary staging

c

Invasive or

in situ cancer

See appropriate

guideline

PHYLL-1

Phyllodes Tumor




Guidelines Index

Breast Cancer TOC


PHYLLODES TUMOR RECURRENCE

CLINICAL PRESENTATION WORKUP FINDINGS TREATMENT



Locally recurrent breast

mass following excision

of phyllodes tumor

�

�

�

�

�

History and physical

exam

Ultrasound

Mammogram

Tissue sampling

(histology preferred)

Consider chest imaging

No metastatic

disease

Metastatic

disease

Re-excision with wide

margins without

axillary staging

Metastatic disease

management following

principles of soft tissue

sarcoma

See NCCN Soft Tissue

Sarcoma Guidelines

Consider

surgery/radiation

therapy for local

control (category 3)

Consider post-

operative radiation

(category 3)d

dThere is no prospective randomized data supporting the use of radiation treatment with phyllodes tumors. However, in the setting where additional recurrence wouldcreate significant morbidity, eg, chest wall recurrence following salvage mastectomy, radiation therapy may be considered, following the same principles that areapplied to the treatment of soft tissue sarcoma.

PHYLL-2

Phyllodes Tumor




Guidelines Index

Breast Cancer TOC


Clinical suspicion

of Paget’s diseasea

�

�

�

Clinical breast exam

Diagnostic bilateral mammogram,

ultrasound as necessary

Breast MRI (optional)b

Examination or imaging

positive for breast lesion

Examination and imaging

negative for breast lesion

CLINICAL

PRESENTATION

WORKUP



a

bNipple or areolar eczema, ulceration, bleeding, itching.

.See Principles of Dedicated Breast MRI Testing (BINV-B)

See PAGET-2

PAGET-1

Paget’s Disease




Guidelines Index

Breast Cancer TOC


Appropriate

systemic

adjuvant

therapy

�

�

Consider MRI if not

previously done

Full thickness skin

biopsy of involved NAC

Core biopsy of breast

lesion and full

thickness skin biopsy

of involved nipple-

a eola complex (NAC)r

Breast and NAC

biopsy negative

Breast DCIS

and NAC Paget’s

Breast invasive cancer

and NAC Paget’se

Breast negative for

cancer and positive

NAC Paget’s

NAC biopsy positive

for Paget’s

NAC biopsy

negative for Paget’s

Clinical follow-upRe-biopsy if not healing

Mastectomy ± axillary stagingorExcision of breast tumor and excision NAC with

whole breast radiation, consider boost to breast

and NAC sites

c

d

Mastectomy + axillary staging ( )orExcision of breast tumor and excision NAC +

axillary staging ( ) with whole breast

radiation, consider boost to breast and NAC sites

See BINV-C

See BINV-C

Mastectomy + axillary staging ( )orExcision of NAC with whole breast radiation,

consider boost to NAC sitesd

See BINV-C

Clinical follow-upRe-biopsy if not healing

TREATMENT

Examination

or imaging

positive for

breast lesion

Examination

and imaging

negative for

breast lesion

WORKUP



c

d

e

Mastectomy always option with any manifestation of Paget’s disease (see manuscript text).

With Paget’s disease and no associated peripheral cancer, or with associated DCIS, consider tamoxifen 20 mg per day for 5 years.

With associated invasive breast cancer, treat with appropriate systemic adjuvant therapy ( )See BINV-4

PAGET-2

Paget’s Disease




Guidelines Index

Breast Cancer TOC




Pregnant patient with

confirmed breast

cancer diagnosisNo distant metastases

on staging

1st

trimester

2nd trimester/

Early 3rd trimester

Late 3rd

trimester

Discuss

termination:Non-

therapeutic

Continuing

pregnancy

Mastectomy +

axillary staginga,b,c

Begin adjuvant chemotherapy

in 2nd trimester± Adjuvant radiation therapy

post-partum± Adjuvant endocrine therapy

post-partum

a

a

a

Mastectomy or breast-

conserving surgery +

or

Neoadjuvant chemotherapy ,

mastectomy or breast-


post-partum

a

a,b,c

a

a,b,c

axillary

staging

axillary

staging

± Adjuvant radiation therapy


post-partum

a

a

Adjuvant chemotherapy± Adjuvant radiation therapy


post-partum

a

a

a

Mastectomy or breast-


a

a,b,caxillary staging

Adjuvant chemotherapy± Adjuvant radiation therapy


post-partum

a

a

a

aConsiderations and selection of optimal local therapy and systemic therapy are similar to that recommended in non-pregnancy associated breast cancer, see othersections of this guideline. Chemotherapy should not be administered during the first trimester of pregnancy and radiation therapy should not be administered during anytrimester of pregnancy. Most experience with chemotherapy during pregnancy for breast cancer is from regimens that utilize various combinations of doxorubicin,cyclophosphamide and fluorouracil. Consideration for post-partum chemotherapy are the same as for non-pregnancy associated breast cancer.

Due to limited data the use of isosulfan blue is not recommended in pregnant patients.

b

cSee Surgical Axillary Lymph Node Staging (BINV-C).

CLINICAL PRESENTATION PRIMARY TREATMENTa ADJUVANT TREATMENTa

PREG-1





Guidelines Index

Breast Cancer TOC


Table 1

American Joint Committee on Cancer (AJCC)TNM Staging System For Breast Cancer

Primary Tumor (T)

TX

T0

Tis

Tis (DCIS)

Tis (LCIS)

Tis (Paget's)

T1

T2

T3

T4

Regional Lymph Nodes (N)

Clinical

NX

N0

N1

N2

N3

Definitions for classifying the primary tumor (T) are the same for clinicaland for pathologic classification. If the measurement is made by thephysical examination, the examiner will use the major headings (T1, T2, orT3). If other measurements, such as mammographic or pathologicmeasurements, are used, the subsets of T1 can be used. Tumors shouldbe measured to the nearest 0.1 cm increment.

Primary tumor cannot be assessed

No evidence of primary tumor

Carcinoma in situ

Ductal carcinoma in situ

Lobular carcinoma in situ

Paget's disease of the nipple with no tumor

Note: Paget's disease associated with a tumor is classified according to thesize of the tumor.

Tumor 2 cm or less in greatest dimension

T1mic Microinvasion 0.1 cm or less in greatest dimension

T1a Tumor more than 0.1 cm but not more than 0.5 cm ingreatest dimension

T1b Tumor more than 0.5 cm but not more than 1 cm in greatestdimension

T1c Tumor more than 1 cm but not more than 2 cm in greatestdimension

Tumor more than 2 cm but not more than 5 cm in greatestdimension

Tumor more than 5 cm in greatest dimension

Tumor of any size with direct extension to (a) chest wall or(b) skin, only as described below

T4a Extension to chest wall, not including pectoralis muscle

T4b Edema (including peau d'orange) or ulceration of the skin ofthe breast, or satellite skin nodules confined to the samebreast

T4c Both T4a and T4b

T4d Inflammatory carcinoma

Regional lymph nodes cannot be assessed (e.g., previouslyremoved)

No regional lymph node metastasis

Metastasis to movable ipsilateral axillary lymph node(s)

Metastases in ipsilateral axillary lymph nodes fixed ormatted, or in * ipsilateral internalmammary nodes in the of clinically evident axillarylymph node metastasis

N2a Metastases in ipsilateral axillary lymph nodes fixed to oneanother (matted) or to other structures

N2b Metastasis only in * ipsilateral internalmammary nodes and in the of clinically evidentaxillary lymph node metastasis

Metastasis in ipsilateral infraclavicular lymph node(s) withor without axillary lymph node involvement, or in

* ipsilateral internal mammary lymph node(s) andin the of clinically evident axillary lymph nodemetastasis; or metastasis in ipsilateral supraclavicularlymph node(s) with or without axillary or internal mammarylymph node involvement

N3a Metastasis in ipsilateral infraclavicular lymph node(s)

N3b Metastasis in ipsilateral internal mammary lymph node(s)and axillary lymph node(s)

N3c Metastasis in ipsilateral supraclavicular lymph node(s)

* is defined as detected by imaging studies (excludinglymphoscintigraphy) or by clinical examination or grossly visiblepathologically.

clinically apparentabsence


clinicallyapparent

presence

Clinically apparent

Staging

ST-1

Staging continued on next page (ST-2)

Breast Cancer




Guidelines Index

Breast Cancer TOC


Table 1 (continued)

Pathologic (pN)a

pNX

pN0

pN1

pN2

pN3

Regional lymph nodes cannot be assessed (e.g., previouslyremoved, or not removed for pathologic study)

No regional lymph node metastasis histologically, noadditional examination for isolated tumor cells (ITC)

Note: Isolated tumor cells (ITC) are defined as single tumor cells or smallcell clusters not greater than 0.2 mm, usually detected only byimmonohistochemical (IHC) or molecular methods but which may beverified on H&E stains. ITCs do not usually show evidence of malignantactivity e.g., proliferation or stromal reaction.

pN0(i-) No regional lymph node metastasis histologically, negativeIHC

pN0(i+) No regional lymph node metastasis histologically, positiveIHC, no IHC cluster greater than 0.2 mm

pN0(mol-) No regional lymph node metastasis histologically, negativemolecular findings (RT-PCR)

pN0(mol+) No regional lymph node metastasis histologically, positivemolecular findings (RT-PCR)

Classification is based on axillary lymph node dissection with or withoutsentinel lymph node dissection. Classification based solely on sentinellymph node dissection without subsequent axillary node dissection isdesignated (sn) for “sentinel node,” e.g., pN0(i+) (sn).

RT-PCR: reverse transcriptase/polymerase chain reaction.

Metastasis in 1 to 3 axillary lymph nodes, and/or in internalmammary nodes with microscopic disease detected bysentinel lymph node dissection but not **

pN1mi Micrometastasis (greater than 0.2 mm, none greater than2.0 mm)

pN1a Metastasis in 1 to 3 axillary lymph nodes

pN1b Metastasis in internal mammary nodes with microscopicdisease detected by sentinel lymph node dissection but not

**

pN1c Metastasis in 1 to 3 axillary lymph nodes and in internalmammary nodes with microscopic disease detected bysentinel lymph node dissection but not .**(If associated with greater than 3 positive axillary lymphnodes, the internal mammary nodes are classified as pN3bto reflect increased tumor burden)

Metastasis in 4 to 9 axillary lymph nodes, or in* internal mammary lymph nodes in the of

axillary lymph node metastasis

pN2a Metastasis in 4 to 9 axillary lymph nodes (at least one tumordeposit greater than 2.0 mm)

pN2b Metastasis in * internal mammary lymphnodes in the of axillary lymph node metastasis

Metastasis in 10 or more axillary lymph nodes, or ininfraclavicular lymph nodes, or in *ipsilateral internal mammary lymph nodes in theof 1 or more positive axillary lymph nodes; or in more than 3axillary lymph nodes with clinically negative microscopicmetastasis in internal mammary lymph nodes; or inipsilateral supraclavicular lymph nodes

pN3a Metastasis in 10 or more axillary lymph nodes (at least onetumor deposit greater than 2.0 mm), or metastasis to theinfraclavicular lymph nodes

pN3b Metastasis in * ipsilateral internalmammary lymph nodes in the of 1 or morepositive axillary lymph nodes; or in more than 3 axillarylymph nodes and in internal mammary lymph nodes withmicroscopic disease detected by sentinel lymph nodedissection but not **

pN3c Metastasis in ipsilateral supraclavicular lymph nodes

* is defined as detected by imaging studies (excludinglymphoscintigraphy) or by clinical examination.

** is defined as not detected by imaging studies(excluding lymphoscintigraphy) or by clinical examination.

b

b

a

b

clinically apparent

clinically apparent

clinically apparent

clinicallyapparent absence


clinically apparentpresence

clinically apparentpresence

clinically apparent

Clinically apparent

Not clinically apparent

ST-2

Staging continued on next page (ST-3)

Breast Cancer




Guidelines Index

Breast Cancer TOC


Table 1 (continued)

Distant Metastasis (M)

MX

M0

M1

STAGE GROUPING

Distant metastasis cannot be assessed

No distant metastasis

Distant metastasis

HISTOPATHOLOGIC TYPE

In situ Carcinomas

Invasive Carcinomas

The histopathologic types are thefollowing:

NOS (not otherwise specified)

Intraductal

Paget's disease and intraductal

NOS

Ductal

Inflammatory

Medullary, NOS

Medullary with lymphoid stroma

Mucinous

Papillary (predominantlymicropapillary pattern)

Tubular

Lobular

Paget's disease and infiltrating

Undifferentiated

Squamous cell

Adenoid cystic

Secretory

Cribriform

Stage 0

Stage I

Stage IIA

Stage IIB

Stage IIIA

Stage IIIB

Stage IIIC

Stage IV

Tis N0 M0

T1* N0 M0

T0 N1 M0

T1* N1 M0

T2 N0 M0

T2 N1 M0

T3 N0 M0

T0 N2 M0

T1* N2 M0

T2 N2 M0

T3 N1 M0

T3 N2 M0

* T1 includes T1mic

T4 N0 M0

T4 N1 M0

T4 N2 M0

Any T N3 M0

Any T Any N M1

Note: Stage designation may bechanged if post-surgical imagingstudies reveal the presence of distantmetastases, provided that the studiesare carried out within 4 months ofdiagnosis in the absence of diseaseprogression and provided that thepatient has not received neoadjuvanttherapy.

HISTOPATHOLOGIC GRADE (G)

HISTOLOGIC GRADE (NOTTINGHAM COMBINED HISTOLOGIC GRADE ISRECOMMENDED)

GX

G1

G2

G3

All invasive breast carcinomas with the exception of medullary carcinomashould be graded. The Nottingham combined histologic grade (Elston-Ellismodification of Scarff-Bloom-Richardson grading system) is recommended.The grade for a tumor is determined by assessing morphologic features (tubuleformation, nuclear pleomorphism, and mitotic count), assigning a value of 1(favorable) to 3 (unfavorable) for each feature, and adding together the scoresfor all three categories. A combined score of 3-5 points is grade 1; a combinedscore of 6-7 points is grade 2; a combined score of 8-9 points is grade 3.

Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. Thevalue of histologic grade in breast cancer: experience from a large study withlong-term follow-up. Histopatholology 1991;19:403-410.

Fitzgibbons PL, Page DL, Weaver D et al. Prognostic factors in breast cancer.College of American Pathologists consensus statement 1999. Arch Pathol LabMed 2000;124:966-978.

Grade cannot be assessed

Low combined histologic grade (favorable)

Intermediate combined histologic grade (moderately favorable)

High combined histologic grade (unfavorable)

Used with the permission of the American Joint Committee on Cancer (AJCC),Chicago, Illinois. The original and primary source for this information is theAJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag New York. (For more information, visit .) Anycitation or quotation of this material must be credited to the AJCC as its primarysource. The inclusion of this information herein does not authorize any reuse orfurther distribution without the expressed, written permission of Springer-VerlagNew York, Inc., on behalf of the AJCC.

1,2

1

2.

www.cancerstaging.net

ST-3

Breast Cancer

http://www.cancerstaging.net

Version 2.2007, 03/28/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. MS-1

Guidelines IndexBreast Cancer TOC

Staging, MS, ReferencesPractice Guidelinesin Oncology – v.2.2007 NCCN

® Breast Cancer

Manuscript

NCCN Categories of Consensus

Category 1: There is uniform NCCN consensus, based on high-level evidence, that the recommendation is appropriate.

Category 2A: There is uniform NCCN consensus, based on lower-level evidence including clinical experience, that the recommendation is appropriate.

Category 2B: There is nonuniform NCCN consensus (but no major disagreement), based on lower-level evidence including clinical experience, that the recommendation is appropriate.

Category 3: There is major NCCN disagreement that the recommendation is appropriate.

All recommendations are category 2A unless otherwise noted.

Overview The American Cancer Society estimates that 214,640 new cases of breast cancer will be diagnosed and 41,430 will die of breast cancer in the United States in 2006.1 Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death.

The incidence of breast cancer has increased steadily in the United States over the past few decades, but breast cancer mortality appears to be declining,1,2 suggesting a benefit from early detection and more effective treatment.

The etiology of the vast majority of breast cancer cases is unknown. However, numerous risk factors for the disease have been established. These risk factors include: female gender; increasing patient age;

family history of breast cancer at a young age; early menarche; late menopause; older age at first live childbirth; prolonged hormone replacement therapy; previous exposure to therapeutic chest wall irradiation; benign proliferative breast disease; and genetic mutations such as the BRCA1/2 genes. However, except for female gender and increasing patient age, these risk factors are associated with only a minority of breast cancers. Women with a strong family history of breast cancer should be evaluated according to the NCCN Genetic/Familial High-Risk Assessment Guidelines. Women at increased risk for breast cancer (generally those with a greater than 1.67% 5-year risk of breast cancer using the Gail model of risk assessment 3) may consider risk reduction strategies (see NCCN Breast Cancer Risk Reduction Guidelines).

Proliferative abnormalities of the breast are limited to the lobular and ductal epithelium. In both the lobular and ductal epithelium, a spectrum of proliferative abnormalities may be seen, including hyperplasia, atypical hyperplasia, in situ carcinoma, and invasive carcinoma.4 Approximately 85% to 90% of invasive carcinomas are ductal in origin. The invasive ductal carcinomas include unusual variants of breast cancer, such as colloid or mucinous, adenoid cystic, and tubular carcinomas, which have especially favorable natural histories.

Staging Effective January 2003, the American Joint Committee on Cancer (AJCC) implemented a revision of the Cancer Staging Manual (sixth edition) containing important changes and additions in the TNM staging system for breast cancer (Table 1).5, 6 This revision differs from the 1997 edition of the AJCC staging by incorporating the increasing use of novel imaging and pathology techniques employed at diagnosis (eg, sentinel node biopsy and immunohistochemistry [IHC] evaluation of nodes) and the number of lymph nodes involved as a factor in staging allocation.




® Breast Cancer

The most substantial changes are:

1. Micrometastases to ipsilateral axillary lymph nodes are distinguished from isolated tumor cells on the basis of size and histological evidence of malignant activity. All metastatic lesions to ipsilateral axillary lymph nodes no larger than 0.2 mm, whether detected by hematoxylin and eosin (H&E) staining or IHC, will be described as pN0(i+). pN0(i-) is used to indicate no detectable tumor cells by either H&E or IHC. The designation pN1mi with no additional identifiers will be used for micrometastases greater than 0.2 mm but no greater than 2.0 mm in greatest dimension.7

2. Identifiers are added to indicate the use of sentinel lymph node resection and IHC or molecular pathology techniques.

3. The number of involved nodes as determined by routine H&E staining (preferred method) or by IHC staining impacts pathologic N staging (pN1 if 1 to 3 lymph nodes, pN2 if 4 to 9 lymph nodes, and pN3 if 10 or more lymph nodes are involved).

4. Metastases to infraclavicular nodes are categorized as N3 disease. 5. Metastases to internal mammary (IM) nodes impact staging

according to the method of detection and presence or absence of concomitant axillary lymph node involvement (N1 disease if involved IM lymph nodes are detected exclusively using sentinel lymph node detection procedure; N2 disease if detected using any other imaging study or clinical examination; or N3 disease if concomitant axillary lymph node involvement is present).

6. Metastasis to ipsilateral supraclavicular lymph nodes is no longer considered M1 disease and is classified as N3 disease.

Although determination of the specific TNM status has become more complex (especially with regard to lymph node staging), the allocation of specific TNM combinations to different stage groupings remains the same, with the exception of the creation of stage IIIC to specifically identify patients with TanyN3M0 disease. This revised staging system

recognizes the heterogeneity of breast cancer and the need to create uniform data collection standards to better assess both the long-term outcome of specific patient subgroups and the impact of novel imaging or pathology techniques.6

Pathology Assessment A central component of the treatment of breast cancer is full knowledge of extent of disease and biologic features. These factors contribute to the determination of the stage of disease, assist in the estimation of the risk that the cancer will recur, and provide information that predicts response to therapy (eg, hormone receptors and human epidermal growth factor receptor 2 [HER2]). These factors are determined by examination of excised tissue and provided in a written pathology report. Accurate pathology reporting requires communication between the clinician and the pathologist relating to relevant patient history, prior breast biopsies, prior irradiation to the chest, pregnancy status, characteristics of the abnormality biopsied (eg, palpable, mammographically detected, microcalcifications), clinical state of lymph nodes, presence of inflammatory change or other skin abnormality, and any prior treatment administered (eg, chemotherapy or radiotherapy). The specimens should be oriented for the pathologist, and specific requests for determination of biomarkers should be stated (eg, estrogen receptor, progesterone receptor, and HER2 status). The use of consistent, unambiguous standards for reporting is strongly encouraged. Data from both national and local surveys show that as many as 50% of pathology reports for breast cancer are missing some elements critical to patient management.8, 9 Significant omissions include failure to orient and report surgical margins, and failure to report tumor grade consistently.

The College of American Pathologists (CAP) has developed pathology reporting protocols to promote complete and standardized reporting of malignant specimens. CAP provides a protocol for each disease site




® Breast Cancer

that includes cancer case summaries (checklists) along with background documentation. These checklists form the basis for a synoptic, standardized reporting of pathologic findings. The checklists are available without charge through the CAP website at www.cap.org.

Consistent, unambiguous, and complete pathology reporting is a cornerstone of quality breast cancer care, and the Panel endorses the use of the CAP protocols for reporting the pathological analysis of all breast specimens.

Treatment Approach Conceptually, the treatment of breast cancer includes the treatment of local disease with surgery, radiation therapy (RT), or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy or combinations of these. The need for and selection of various local or systemic therapies are based on a number of prognostic and predictive factors. These factors include tumor histology, clinical and pathologic characteristics of the primary tumor, axillary node status, tumor hormone receptor content, tumor HER2 status, presence or absence of detectable metastatic disease, patient comorbid conditions, patient age, and menopausal status. Breast cancer does occur in men, and men with breast cancer should be treated similarly to postmenopausal women, except that the use of aromatase inhibitors is ineffective without concomitant suppression of testicular steroidogenesis.10,11 Patient preference is a major component of the decision-making process, especially in situations in which survival rates are equivalent among the available treatment options.

In terms of treatment, breast cancer may be divided into 1) the pure noninvasive carcinomas, which include LCIS and ductal carcinoma in situ (DCIS) (stage 0); 2) operable, local-regional invasive carcinoma with or without associated noninvasive carcinoma (clinical stage I, stage II, and some stage IIIA tumors); 3) inoperable local-regional

invasive carcinoma with or without associated noninvasive carcinoma (clinical stage IIIB, stage IIIC, and some stage IIIA tumors); and 4) metastatic or recurrent carcinoma (stage IV).

The Breast Cancer Clinical Practice Guidelines presented here are the work of the members of the NCCN Breast Cancer Clinical Practice Guidelines Panel. Categories of evidence were assessed and are noted on the algorithms and in the text. Although not explicitly stated at every decision point of the Guidelines, patient participation in prospective clinical trials is the preferred option of treatment for all stages of breast cancer.

Pure Noninvasive Carcinomas (Stage 0)

Both LCIS and DCIS may be difficult to distinguish from atypical hyperplasia or from carcinomas with early invasion.12,13 Therefore, pathology review of all cases is recommended. Bilateral diagnostic mammography should be performed to identify the presence of multiple primary tumors and to estimate the extent of the noninvasive lesion.

The goal of treatment of pure in situ carcinoma is either preventing the occurrence of invasive disease or diagnosing the development of an invasive component when still localized to the breast. Patients found to have invasive disease, even if microinvasive, on pathology review or at the time of re-excision, mastectomy, or axillary lymph node staging should be treated according to the stage-appropriate guideline for invasive carcinoma.

Lobular carcinoma in situ Observation alone is the preferred option for women diagnosed with LCIS because their risk of developing invasive carcinoma is low (approximately 21% over 15 years).14 The histologies of the invasive carcinomas tend to be favorable, and deaths from second invasive cancers are unusual in appropriately monitored women.15 Bilateral

http://www.cap.org




® Breast Cancer

mastectomy, with or without reconstruction, can be considered in special circumstances such as in women with BRCA1/2 mutations or a strong family history of breast cancer, or in women with very high levels of anxiety.

The risk of an invasive breast cancer after a diagnosis of LCIS is equal in both breasts.16 If mastectomy is considered as a risk reduction strategy, then a bilateral procedure is required to optimally minimize risk. Women treated with bilateral mastectomy are appropriate candidates for breast reconstruction.

There is evidence to support the existence of histologically aggressive variants of LCIS (eg, pleomorphic LCIS) which may have a greater potential than classic LCIS to develop into invasive lobular carcinoma.17 However, outcome data regarding treatment of patients with pleomorphic LCIS are lacking, due, in part, to a paucity of histologic categorization of variants of LCIS. Therefore, recommendations on the treatment of pleomorphic LCIS as a distinct entity of LCIS have not been made by the Panel.

Women with LCIS, whether they undergo observation only or are treated with bilateral mastectomy, have an excellent prognosis. Recent data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial show that tamoxifen given for 5 years is associated with an approximately 56% reduction (hazard ratio 0.44; 95% CI 0.16-1.06) in the risk of developing invasive breast cancer among women with LCIS.18, 19 Results from the NSABP Study of Tamoxifen and Raloxifene (STAR) trial have shown raloxifene to be as effective as tamoxifen in reducing the risk of invasive cancer in postmenopausal patients with LCIS.20 Therefore, the use of tamoxifen in premenopausal women or tamoxifen or raloxifene in postmenopausal women should be considered as a risk reduction strategy in women with LCIS who are followed with observation (category 1). (For

recommendations on risk reduction, see also the NCCN Breast Cancer Risk Reduction Guidelines.)

Follow-up of patients with LCIS includes physical examinations every 6 to 12 months for 5 years and then annually. Annual diagnostic mammography is recommended in patients being followed with clinical observation.

Ductal carcinoma in situ Patients with DCIS and evidence of widespread disease (ie, disease in 2 or more quadrants) on mammography or other imaging, physical examination, or biopsy require a total mastectomy without lymph node dissection. For the vast majority of patients with more limited disease and in whom negative margins are achieved with the initial excision or with re-excision, breast-conserving therapy or total mastectomy are appropriate treatment options. Although mastectomy provides maximum local control, the long-term, cause-specific survival with mastectomy appears to be equivalent to that with excision and whole breast irradiation.21-23 Women treated with mastectomy are appropriate candidates for breast reconstruction. Contraindications to breast-conserving therapy with radiation therapy are listed in the algorithm (see BINV-F).

Prospective randomized trials have shown that the addition of whole breast irradiation to a margin-free excision of pure DCIS decreases the rate of in-breast disease recurrence, but does not affect overall survival.23,24 Although some non-controlled evidence suggests that selected patients have a low risk of in breast recurrence with excision alone without breast irradiation,25, 26 based on high-level evidence from randomized trials, the NCCN guideline recommends the use of radiation after local excision in all patients with DCIS 0.5 cm or greater in diameter. The use of whole breast radiation after breast-conserving surgery reduces the relative risk of a local failure by approximately one




® Breast Cancer

half. The use of a radiation boost (by photons, brachytherapy, or electron beam) to the tumor bed is recommended to maximize local control, especially in patients 50 years of age or younger. Many factors, including patient age, tumor size, tumor grade, and margin width, impact recurrence risk. The definition of a negative margin has not been firmly established in DCIS. There appears to be a consensus that margins greater than 10 mm are adequate and margins less than 1 mm are inadequate, but no uniform consensus exists for margin status between these values. Results from a retrospective study of 445 patients with pure DCIS treated by excision alone indicated that margin width was the most important independent predictor of local recurrence, although the trend for decreasing local recurrence risk with increasing margin width was most apparent with margins less than 1mm and greater than or equal to 6 mm.27 Further complicating the issue of margin width is the impact of the fibroglandular boundary – the pectoral fascia and the superficial skin where narrower tumor free margins may provide adequate local control. Finally, because the choice of local treatment does not impact disease-related survival, the individual patient’s acceptance of the potential for an increased risk of local recurrence must be considered.

Axillary dissection is not recommended for patients with pure DCIS. However, a small proportion of women with apparent pure DCIS on initial biopsy will be found to have invasive breast cancer at the time of the definitive surgical procedure and thus ultimately require axillary lymph node staging. In patients with apparent pure DCIS to be treated with mastectomy or with excision in an anatomic location (eg, tail of the breast), which could compromise the performance of a future sentinel lymph node procedure, a sentinel lymph node procedure may be considered.28-30

Limited evidence suggests that very small (less than 0.5 cm), unicentric, low-grade DCIS of the solid, cribriform or papillary subtypes may be managed with any of the following options:

1) Excision plus RT; 2) Total mastectomy, with or without reconstruction; 3) Excision alone followed by clinical observation.

Patients with mammographically detectable DCIS who elect breast conservation therapy should undergo post-excision mammography of the involved breast and specimen radiography to ensure that all mammographically detectable disease has been excised. Alternatively, some Panel members believe that specimen radiographs are adequate documentation of complete excision if such radiographs show that the abnormality (the mass and/or microcalcifications) is clearly within the specimen. Clips are used by some NCCN institutions to demarcate the biopsy area because DCIS may be clinically occult and further surgery may be required, pending the margin status review by pathology.

DCIS falls between atypical ductal hyperplasia and invasive ductal carcinoma within the spectrum of breast proliferative abnormalities. The NSABP Breast Cancer Prevention Trial showed an 86% reduction in the occurrence of invasive breast cancer in patients with atypical ductal hyperplasia treated with tamoxifen.18,19 These data also showed that tamoxifen led to a substantial reduction in the risk of developing benign breast disease.31 The Early Breast Cancer Trialists’ overview analysis showed that, with 5 years of tamoxifen therapy, women with estrogen receptor- (ER) positive or receptor-unknown invasive tumors had a 52% reduction in the annual odds of recurrence of invasive breast cancer.2

Similarly, the NSABP B-24 trial found a benefit from tamoxifen for women with DCIS after treatment with breast conservation surgery (BCS) and RT. In that study, women with DCIS who were treated with breast-conserving therapy were randomized to receive placebo or




® Breast Cancer

tamoxifen. The women treated with tamoxifen had a 5% absolute reduction in recurrence risk and a 37% reduction in relative risk. The women receiving tamoxifen had an 8.2% total incidence of breast cancer (4.1% invasive and 4.2% noninvasive) compared with a 13.4% incidence of breast cancer (7.2% invasive and 6.2% noninvasive) in the placebo-treated group at a median follow-up of 74 months.32 A retrospective analysis of estrogen receptor expression in NSABP B-24 suggests that increased levels of ER expression predict for tamoxifen benefit in terms of reduction of risk for the development of both ipsilateral and contralateral breast cancer following breast-conserving therapy.33

Tamoxifen treatment, therefore, may be considered for women with DCIS treated with breast-conserving therapy, especially in those with ER-positive DCIS (category 1 for those undergoing BCS + RT; category 2A for those undergoing excision alone), and in women with DCIS treated with mastectomy (category 2B). The goal of such therapy is to decrease the development of a contralateral, second primary breast cancer (risk reduction therapy) and, in those who received breast-conserving therapy, to reduce the risk of an ipsilateral in breast recurrence (adjuvant therapy).

Follow-up of women with DCIS includes a physical examination every 6 months for 5 years and then annually, as well as yearly diagnostic mammography.

Stage I, IIA, IIB, or T3N1M0 Invasive Breast Cancer The recommended work-up and staging of invasive breast cancer includes history and physical exam, a complete blood cell count, platelet count, liver function tests, chest imaging, bilateral diagnostic mammography, and, if necessary, breast ultrasonography, tumor estrogen and progesterone receptor determinations, HER2 tumor status determination, and pathology review.

Use of MRI to evaluate women considering breast-conserving therapy is optional (category 2B) (see BINV-B). If MRI imaging of the breast is performed, it should be done with a dedicated breast coil, with consultation with the multidisciplinary treatment team, and by a breast imaging team capable of performing MRI-guided biopsy. The limitations of breast MRI include a high percentage of false-positive findings.34, 35 MRI imaging of the breast, therefore, should generally be considered in the staging of breast cancer for patients whose breasts cannot be imaged adequately with mammography and ultrasound (eg, women with very dense breast tissue, women with positive axillary nodal status and occult primary tumor presumed to originate in the breast, or to evaluate the chest wall). Patients should not be denied the option of breast conservation therapy based upon MRI findings alone in the absence of tissue sampling.

Radionuclide bone scanning and abdominal imaging with CT, ultrasound, or MRI are indicated for patients with T3N1M0 disease, if the patient has signs or symptoms related to bone or abdomen, or an elevated alkaline phosphatase. In the remaining patients, bone scan (category 2B) and abdominal imaging (category 2B) are considered optional.

The determination of HER2 status for all newly diagnosed invasive breast cancers is recommended. HER2 status can be assessed by measuring the number of HER2 gene copies (fluorescence in situ hybridization [FISH]), or by a complementary method in which the number of HER2 cell surface receptors is evaluated (immunohistochemistry [IHC]).36 Only 4 methods currently have United States Food and Drug Administration approval for determining the HER2 status of breast cancer tumors. These methods include: 1) the IHC HercepTest® (DAKO, Glostrup, Denmark)37; 2) the IHC Pathway® HER2 test (Ventana Medical Systems, Tucson, AZ)38; 3) the INFORM® HER2 FISH test (Ventana Medical Systems)39; 4) and the PathVysion®




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HER2 FISH test (Vysis, Downers Grove, IL),40 although modifications of these methods are currently in use in many anatomic pathology laboratories. The accuracy of HER2 assays used in clinical practice is a major concern, and results from several studies have shown that false-positive41-45 as well as false-negative41,46 HER2 test results are common. An NCCN Task Force has recently reviewed this topic and issued recommendations on HER2 testing in breast cancer47 which are summarized in the guideline (see BINV-A). The Panel considers either an IHC or FISH test as an acceptable method for making an initial determination of HER2 tumor status provided that the test method has been validated and shown to be at least 95% concordant with another validated method. Evidence for 95% concordance between the HER2 assay used and a validated complementary HER2 testing method is also required. Breast cancer tumors are classified as HER2-positive if they demonstrate HER2 gene amplification by a FISH method or are scored as 3+ by an IHC method. Strategies for evaluating tumors with borderline or indeterminate HER2 status (eg, FISH [Pathvysion®] scores of 1.8-2.2 HER2 genes/chromosome 17/cell, FISH [INFORM®] scores of greater than 4 to less than 6 HER2 genes/cell, or 2+ scores by IHC) are described in the guideline (see BINV-A). HER2 testing should be performed only in laboratories accredited to carry out such testing. Further, these laboratories should have standardized HER2 testing procedures in place, as well as programs to periodically evaluate the proficiency of personnel performing HER2 testing. HER2 test reports must provide information on site of tumor; specimen type; histologic type; fixation method and time; block examined; HER2 testing method used; results of ongoing validation and concordance studies of the HER2 testing methods used in that laboratory, as well as other laboratory quality assurance information. Clinicians should be familiar with the significance of these criteria when making clinical recommendations for an individual patient.

A determination of the HER2 status of the tumor is recommended for prognostic purposes for patients with node-negative breast cancer.48 HER2 tumor status also provides baseline predictive information used in selecting optimal adjuvant/neoadjuvant therapy and in the selection of therapy for recurrent or metastatic disease (category 1). For example, retrospective analyses have demonstrated that anthracycline-based adjuvant therapy is superior to non-anthracycline-based adjuvant chemotherapy in patients with HER2-positive tumors,49-53 and that the dose of doxorubicin may be important in the treatment of tumors that are HER2-positive.54 However, prospective evidence of the predictive utility of HER2 status in early-stage55-58 and metastatic breast cancer59-

61 is currently available only for trastuzumab-containing therapies.

Local-regional treatment A number of randomized trials document that mastectomy with axillary lymph node dissection or breast-conserving therapy with lumpectomy, axillary dissection, and whole breast irradiation (breast-conserving therapy) are medically equivalent primary treatment options in the majority of women with stage I and stage II breast cancers (category 1).62-65 When breast-conserving therapy with lumpectomy and radiation therapy is performed, the Panel finds the data inadequate to support the use of partial breast irradiation outside the confines of a high-quality, prospective clinical trial.66

The use of breast-conserving therapy is absolutely contraindicated for patients who have received previous moderate- or high-dose RT to the breast or chest wall, are pregnant and would require RT during pregnancy, have diffuse suspicious or malignant-appearing microcalcifications on mammography, have widespread disease that cannot be incorporated by local excision through a single incision with a satisfactory cosmetic result, or have a positive pathologic margin (see BINV-E; BINV-F). Patients with a pathologically positive margin may undergo re-excision(s) to achieve a negative pathologic margin. If the




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margins remain positive after re-excision(s), then mastectomy is required for optimal local disease control. In order to adequately assess margins following lumpectomy, the Panel recommends that the surgical specimens be oriented, that the pathologist provide descriptions of the gross and microscopic margin status, and the distance, orientation, and type of tumor (invasive or DCIS) in relation to the closest margin.

Relative contraindications to breast-conserving therapy include active connective tissue disease involving the skin (especially scleroderma and lupus), tumors greater than 5 cm (category 2B), and focally positive pathologic margins (see BINV-F). Those patients with focally positive pathologic margins who do not undergo re-excision should be considered for a higher radiation boost dose to the tumor bed.

Several studies of women with early-stage breast cancer treated with breast-conserving therapy have identified young age as a significant predictor of an increased likelihood of ipsilateral breast tumor recurrence.67-69 Risk factors, such as a family history of breast cancer or a genetic predisposition for breast cancer (eg, BRCA 1/2 or other mutation), are more likely to exist in the population of young women with breast cancer, thereby confounding the independent contributions of age and treatment to clinical outcome.70 Survival outcomes for young women with breast cancer receiving either breast-conserving therapy or mastectomy are similar.71 The Panel recommends that women with breast cancer who are less than 35 years or premenopausal and carriers of a known BRCA 1/2 mutation consider additional risk reduction strategies (see BINV-F; NCCN Breast Risk Reduction Guidelines and NCCN Genetic/Familial High-Risk Assessment Guidelines)

In a study of women with clinical stage I, estrogen receptor-positive breast cancer, who were 70 years of age or older at diagnosis, patients were randomized to receive lumpectomy with whole breast radiation or lumpectomy alone, both with tamoxifen for 5 years. Local-regional

recurrence rates were 1% in the lumpectomy, radiation and tamoxifen arm, and 4% in the lumpectomy plus tamoxifen arm. There were no differences in overall survival, disease-free survival or need for mastectomy.72 Similar results were obtained in another study of similar design.73 The Guidelines allow for the use of breast-conserving surgery (pathologically negative margin required) plus tamoxifen or an aromatase inhibitor without breast irradiation in women age 70 or older with clinically negative lymph nodes and ER positive breast cancer (category 1 with tamoxifen; category 2A with an aromatase inhibitor).

If adjuvant chemotherapy is indicated following breast-conserving surgery, RT should typically be given after chemotherapy is completed.74 Breast-conserving RT may be given concurrent with CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy, but methotrexate should either be withheld during the radiation or limited to no more than 2 doses concurrent with the radiation. Concurrent CMF chemotherapy with RT has been demonstrated to decrease the cosmetic outcome of breast-conserving therapy in some, but not all studies.75-77 The guideline includes a recommendation for regional lymph node RT in patients treated with breast-conserving surgery (see BINV-2) analogous to that recommended in patients treated with post-mastectomy regional lymph node irradiation (see BINV-3; subsequent discussion).

The NCCN Breast Cancer Treatment Guidelines include a guideline for surgical staging of the axilla for stages I, IIA, and IIB breast cancer (see BINV-C). A typical woman with clinical stage I or stage II breast cancer requires pathologic assessment of the axillary lymph node status.

Performance of sentinel lymph node mapping and resection in the surgical staging of the axilla is recommended by the Panel as the preferred method to assess the pathologic status of the axillary lymph nodes for patients with stage I or stage II breast cancer30,78-85 (see BINV-C). This recommendation is supported by results of recent




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randomized clinical trials showing decreased arm and shoulder morbidity (eg, pain, lymphedema, and sensory loss) in patients with breast cancer undergoing sentinel lymph node biopsy compared with patients undergoing standard axillary node dissection.84,86 No significant differences in the effectiveness of the sentinel lymph node procedure or level I and II dissection in determining the presence or absence of metastases in axillary nodes were seen in these studies. However, not all women are candidates for sentinel lymph node resection. The availability of an experienced sentinel lymph node team is mandatory for the use of sentinel lymph node mapping and excision.87, 88 Women who have clinical stage I or II disease and do not have immediate access to an experienced sentinel node team should be considered for referral to an experienced sentinel lymph node team for the definitive surgical treatment of the breast and surgical axillary lymph node staging. In addition, potential candidates for sentinel lymph node mapping and excision should have clinically negative axillary lymph nodes, or a negative core or fine needle aspiration (FNA) biopsy of any clinically suspicious axillary lymph node(s). If the sentinel lymph node cannot be identified or is positive for metastasis, a formal axillary lymph node dissection should be performed (category 2A) or axillary RT administered (category 2B). If lymph node mapping identifies sentinel lymph nodes in the internal mammary chain, internal mammary node excision is considered optional (category 3). In many institutions, sentinel lymph nodes are assessed for the presence of metastases by both H&E staining and cytokeratin IHC. The clinical significance of a lymph node that is negative by H&E staining but positive by cytokeratin IHC is not clear. Because the historical and clinical trial data on which treatment decisions are based have relied on H&E staining, the Panel believes that current treatment decisions should be made based solely on H&E staining (category 3). In the uncommon situation in which H&E staining is equivocal, reliance on the results of cytokeratin IHC is reasonable.

Level I or II axillary dissection is an appropriate staging study in women with invasive breast cancer. Although the option of sentinel lymph node mapping and excision is preferred by the Panel over axillary lymph node dissection as the initial axillary lymph node staging for women with clinically node-negative stage I or stage II breast cancer, it is not a mandatory replacement for a level I and II axillary dissection. Axillary lymph node dissection remains indicated in women found to have axillary lymph node involvement on sentinel lymph node excision. Traditional level I and level II axillary dissection required that at least 10 lymph nodes should be provided for pathologic evaluation to accurately stage the axilla.89,90 Axillary dissection should be extended to include level III nodes only if gross disease is apparent in the level I or II nodes.

Furthermore, in the absence of definitive data demonstrating superior survival with axillary lymph node dissection or sentinel lymph node resection, these procedures may be considered optional in patients who have particularly favorable tumors, patients for whom the selection of adjuvant systemic therapy is unlikely to be affected by the results of the procedure, elderly patients, and patients with serious co-morbid conditions (see BINV-D). Women who do not undergo axillary dissection or axillary lymph node irradiation are at increased risk for ipsilateral lymph node recurrence.91 Women who undergo mastectomy are appropriate candidates for breast reconstruction.

Preoperative chemotherapy for large clinical stage IIA and IIB tumors and T3N1M0 tumors Preoperative chemotherapy should be considered for women with large clinical stage IIA, stage IIB, and T3N1M0 tumors who meet the criteria for breast-conserving therapy except for tumor size and who wish to undergo breast-conserving therapy. In the available clinical trials of preoperative chemotherapy, pretreatment biopsies have been limited to core needle biopsy or FNA cytology. Therefore, in patients anticipated to receive preoperative chemotherapy, core or FNA biopsy of the breast




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tumor should be performed, and core or FNA biopsy of clinically suspicious axillary lymph nodes should be considered. Preoperative chemotherapy is not indicated unless invasive breast cancer is confirmed. The current guideline lists pre-chemotherapy sentinel lymph node resection as the preferred option for surgical axillary staging in those women with clinically negative ipsilateral axillary examinations (see BINV-C). If the sentinel lymph node is histologically negative, omission of the axillary dissection may be considered at the time of local, surgical therapy. If the sentinel lymph node is histologically positive, then level I and II axillary dissection should be performed at the time of definitive surgical therapy. If a pre-chemotherapy sentinel lymph node excision is not performed, then a level I and II axillary dissection (category 2A) or sentinel lymph node excision (category 3) (with level I and II axillary dissection if sentinel lymph node is positive) should be performed at the time of definitive surgical therapy.

In some patients, preoperative chemotherapy results in sufficient tumor response that breast-conserving therapy becomes possible. Because complete or near-complete clinical responses are common, the use of percutaneously placed clips into the breast under mammographic or ultrasound guidance or other method of localizing pre-chemotherapy tumor volume aids in the post-chemotherapy resection of the original area of tumor and is encouraged. The results of the NSABP B-18 trial show that breast conservation rates are higher after preoperative chemotherapy.92 However, preoperative chemotherapy has no demonstrated disease specific survival advantage over postoperative adjuvant chemotherapy in patients with stage II tumors. NSABP B-27 is a 3-arm, randomized phase III trial of women with invasive breast cancer treated with preoperative doxorubicin and cyclophosphamide (AC) chemotherapy for 4 cycles followed by local therapy alone, preoperative AC followed by preoperative docetaxel for 4 cycles followed by local therapy, or AC followed by local therapy followed by 4 cycles of postoperative docetaxel. Results from this study which

involved 2411 women documented a higher rate of complete pathologic response at the time of local therapy in patients treated preoperatively with 4 cycles of AC followed by 4 cycles of docetaxel versus 4 cycles of preoperative AC. Disease-free survival and overall survival have not been shown to be superior following docetaxel treatment in B-27.93 A disease-free survival advantage was observed (hazard ratio 0.71; 95% CI, 0.55 – 0.91; P=0.007) favoring preoperative versus postoperative docetaxel in the subset of patients experiencing a clinical partial response to AC.

A number of chemotherapy regimens have been studied as preoperative chemotherapy in the neoadjuvant setting. The Panel believes that the regimens recommended in the adjuvant setting (see BINV-H) are appropriate to consider in the preoperative chemotherapy setting. In women with HER2-positive tumors treated with neoadjuvant chemotherapy, the addition of neoadjuvant trastuzumab to paclitaxel followed by FEC chemotherapy was associated with an increase in the pathologic complete response rate from 26% to 65.2% (P=0.016).94 Thus, the incorporation of trastuzumab into neoadjuvant chemotherapy regimens appears important in HER2-positive tumors.

Several randomized trials have assessed the value of neoadjuvant endocrine therapy in postmenopausal women with estrogen receptor-positive breast cancer. These studies have generally compared the rates of objective response and rates of breast-conserving surgery among treatment with tamoxifen, anastrozole, anastrozole plus tamoxifen, or letrozole. These studies consistently demonstrate that the use of either anastrozole or letrozole alone provides superior rates of breast-conserving surgery and usually objective response.95, 96 On the basis of these trials, preoperative hormonal therapy with an aromatase inhibitor is an option in the treatment of postmenopausal women with hormone receptor-positive disease.




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If the tumor responds to preoperative chemotherapy, lumpectomy plus (if pre-chemotherapy sentinel lymph node staging was not done or was positive) axillary lymph node dissection (category 2A) or (if pre-chemotherapy axillary lymph node staging not performed) sentinel lymph node procedure (category 3) may be considered if the requirements for breast-conserving therapy are fulfilled (see BINV-11; BINV-12). If a pre-chemotherapy sentinel lymph node procedure was performed and the sentinel lymph node was pathologically negative, then further axillary lymph node staging is not necessary. If a pre-chemotherapy sentinel lymph node procedure was performed and the sentinel lymph node was positive, then a level I/II axillary lymph node dissection should be performed. Breast-conserving surgery should be followed by individualized chemotherapy such as taxanes (category 2B) as well as breast and regional lymph node irradiation. Whether the internal mammary lymph nodes should be included in the regional lymph node field generated substantial controversy among Panel members (category 3). If after several cycles of preoperative chemotherapy, the tumor fails to respond, the response is minimal, or if the disease progresses at any point, a mastectomy plus axillary dissection, with or without breast reconstruction, should be performed. Postoperative treatment for these patients consists of individualized chemotherapy, endocrine therapy in women with estrogen and/or progesterone receptor-positive tumors, and RT to the chest wall and supraclavicular lymph nodes. Inclusion of the internal mammary lymph nodes in the radiotherapy field can be considered, but this recommendation generated substantial controversy among Panel members (category 3). Postmastectomy RT in patients with T2N0M0 tumors may be considered optional.

Radiation therapy after mastectomy Node positive disease Three randomized clinical trials have shown that a disease-free and overall survival advantage is conferred by the addition of chest wall and

regional lymph node irradiation in women with positive axillary lymph nodes after mastectomy and axillary lymph node dissection.97-101 In these trials, not only the ipsilateral chest wall but also the ipsilateral local-regional lymph nodes were irradiated. These studies contrast, however, with a number of other studies, including a randomized trial from an NCCN institution that failed to show a survival advantage with postmastectomy chest wall and regional node irradiation.102 However, on the basis of the studies suggesting a survival advantage with postmastectomy chest wall and regional lymph node irradiation in node-positive breast cancer, the current Guidelines call for the consideration of postmastectomy irradiation in women with such cancers.

For women with 1 to 3 involved axillary lymph nodes, the Guidelines recommend consideration of radiation to the chest wall and supraclavicular area after chemotherapy (category 1), with consideration also given to the inclusion of the ipsilateral internal mammary field (category 3). The recommendation for chest wall and supraclavicular irradiation in women with 1-3 involved axillary lymph nodes generated substantial controversy among Panel members. Some Panel members believe chest wall and supraclavicular irradiation should be used routinely after mastectomy and chemotherapy in this subgroup of patients. However, other Panel members believe radiation should be considered in this setting but should not be mandatory given the studies that do not show an advantage. This is an unusual situation in which high-level evidence (category 1) exists but is contradictory.63,98,99,101 Women with 1 to 3 involved axillary lymph nodes and with tumors greater than 5 cm or with tumors with positive pathologic margins postmastectomy should receive post-chemotherapy RT to the chest wall and supraclavicular areas (category 1) with consideration of inclusion of the ipsilateral internal mammary field (category 3).




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There is considerable disagreement regarding the inclusion of the ipsilateral internal mammary field. Some Panel members believe that irradiation of the internal mammary nodes is unnecessary and produces too much morbidity. Others believe internal mammary field irradiation should be included, as it was in the studies that demonstrated an advantage for postmastectomy, post-chemotherapy RT. Therefore, this recommendation is identified as category 3.

Women with 4 or more positive axillary lymph nodes are at substantially increased risk for local recurrence of disease. The use of postmastectomy, post-chemotherapy chest wall and regional lymph node irradiation is recommended (category 1). The use of prophylactic chest wall RT in this setting substantially reduces the risk of local recurrence.63 Again, there was substantial disagreement among Panel members regarding the inclusion of the ipsilateral internal mammary field (category 3).

Node negative disease Features in node-negative tumors that predict a high rate of local recurrence include primary tumors greater than 5 cm and close (less than 1 mm) or positive pathologic margins. Chest wall RT is recommended in patients with negative axillary lymph nodes and tumors greater than 5 cm or with positive pathologic margins.103 Consideration should be given to radiation to the ipsilateral supraclavicular area (category 2B) and to the ipsilateral internal mammary lymph nodes (category 3). Chest wall RT should be considered for patients with negative axillary lymph nodes and close (less than 1 mm) pathologic margins. RT is not recommended for patients with negative margins, tumors 5 cm or smaller, and no positive axillary lymph nodes.

Systemic adjuvant therapy After surgical treatment, adjuvant systemic therapy should be considered. The most recently published updates of the Early Breast Cancer Trialists’ Collaborative Group overview analyses of adjuvant polychemotherapy and tamoxifen show convincing reductions in the odds of recurrence and of death in all age groups under 70 years for polychemotherapy and in all age groups for tamoxifen.2 Thus, for those under age 70, the current Guidelines recommend adjuvant therapy without regard to patient age (category 1). The decision to use systemic adjuvant therapy requires considering and balancing risk for disease recurrence with local therapy alone, the magnitude of benefit from applying adjuvant therapy, toxicity of the therapy and comorbidity.104, 105

The decision-making process requires a collaboration involving the health care team and the patient.

Estimating risk of relapse or death and benefits of systemic treatment A number of prognostic factors predict for future recurrence or death from breast cancer. The strongest prognostic factors are patient age, comorbidity, tumor size, tumor grade, number of involved axillary lymph nodes, and possibly HER2 tumor status. Algorithms have been published estimating rates of recurrence,104 and a validated computer-based model (Adjuvant! Online; www.adjuvantonline.com) is available to estimate 10-year disease-free and overall survival that incorporates all of the above prognostic factors except for HER2 tumor status.105,106

These tools aid the clinician in objectively estimating outcome with local treatment only, and also assist in estimating the absolute benefits expected from systemic adjuvant endocrine therapy and chemotherapy. These estimates may be utilized by the clinician and patient in their shared decision-making regarding the toxicities, costs, and benefits of systemic adjuvant therapy.107

Use of DNA microarray technologies to characterize breast cancer has allowed the development of classification systems of breast cancer by

http://www.adjuvantonline.com




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gene expression profile.108 Five major subtypes of breast cancer have been identified by DNA microarray gene expression profiling: ER-positive/HER2-negative (Luminal A and Luminal B subtypes); ER-negative/HER2-negative (Basal subtype); HER2-positive; and tumors that have characteristics similar to normal breast tissue (Normal breast-like).109-111 In retrospective analyses, these gene expression subtypes are associated with differing relapse-free and overall survival. A similar approach has been used to define more limited sets of genes for prognostic and predictive purposes.112-114

Another gene-based approach is the multi-gene assay using reverse transcription polymerase chain reaction (RT-PCR) on RNA isolated from paraffin-embedded breast cancer tissue (Oncotype Dx). On retrospective analysis of two trials (NSABP B-14 and B-20) performed in women with hormone receptor-positive, axillary lymph node-negative invasive breast cancer, this assay system was able to quantify risk of recurrence as a continuous variable (eg, Oncotype Dx recurrence score) and to predict responsiveness to both tamoxifen and CMF or methotrexate/5-fluorouracil/leucovorin chemotherapy.115,116 A comparison of simultaneous analyses of breast cancer tumors using 5 different gene-expression models indicated that 4 of these methods provided similar predictions of clinical outcome.117

While many of the DNA microarray technologies are able to stratify patients into prognostic and/or predictive subsets on retrospective analysis, the gene subsets appear to differ from study to study, and prospective clinical trials testing the utility of these techniques have yet to be reported. The Panel anticipates that the use of gene microarrays or RT-PCR analysis of RNA will play an important role in providing information regarding prognostic and predictive characteristics of subsets of patients with breast cancer. The Panel awaits additional studies prior to issuing a specific recommendation regarding this or similar assays.

Axillary lymph node negative tumors Small tumors (up to 0.5 cm in greatest diameter) that do not involve the lymph nodes are so favorable that adjuvant systemic therapy is of minimal incremental benefit and is not recommended as treatment of the invasive breast cancer. Tamoxifen may be considered to reduce the risk of a second contralateral breast cancer, especially in those with estrogen receptor-positive disease. The NSABP database demonstrated a correlation between the estrogen receptor status of a new contralateral breast tumor and the original primary tumor, which reinforced the notion that tamoxifen is unlikely to be an effective strategy to reduce the risk of contralateral breast cancer in patients diagnosed with estrogen receptor-negative tumors.118 Patients with invasive ductal or lobular tumors 0.6 to 1 cm in diameter and no lymph node involvement may be divided into patients with a low risk of recurrence and those with unfavorable prognostic features that warrant consideration of adjuvant therapy. Unfavorable prognostic features include intramammary angiolymphatic invasion, high nuclear grade, high histological grade, HER2-positive status, or hormone receptor-negative status (category 2B). The use of endocrine therapy and chemotherapy in these relatively lower risk subsets of women must be based on balancing the expected absolute risk reduction and the individual patient’s willingness to experience toxicity to achieve that incremental risk reduction.

Patients with lymph node involvement or with tumors greater than 1 cm in diameter are appropriate candidates for adjuvant systemic therapy (category 1). For women with lymph node-negative, hormone receptor-negative tumors greater than 1 cm in diameter, chemotherapy is recommended (category 1). For those with lymph node-negative, hormone receptor-positive breast cancer tumors greater than 1 cm, endocrine therapy with chemotherapy is recommended (category 1). The incremental benefit of combination chemotherapy in patients with lymph node-negative, hormone receptor-positive breast cancer may be




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relatively small.119 Therefore, the Panel recommends that tumor hormone receptor status be included as one of the factors considered when making chemotherapy-related treatment decisions for patients with node-negative, hormone receptor-positive breast cancer. Patients for whom this evaluation may be especially important are those with tumors characterized as 0.6-1.0 cm and hormone receptor-positive with unfavorable features, or greater than 1 cm and hormone receptor-positive and HER2-negative (see BINV-5; BINV-6). However, chemotherapy should not be withheld from these patients solely on the basis of estrogen receptor-positive tumor status.2,119,120

The use of both endocrine therapy and chemotherapy must be based on balancing the expected absolute risk reduction and the individual patient’s willingness to experience toxicity to achieve that incremental risk reduction. The use of genomic/gene expression array data which also incorporate additional prognostic/predictive biomarkers (eg, Oncotype Dx recurrence score) may provide additional prognostic and predictive information beyond anatomic staging and determination of ER/PR and HER2 status. Assessment of the role of the genomic/gene expression array technology is difficult because of the retrospective nature of the studies, the evolution of chemotherapy and hormone therapy regimens, and the overall more favorable prognosis of the patients with lymph node-negative disease compared with those enrolled in the historically-controlled clinical trials. Some NCCN institutions consider performing RT-PCR analysis (eg, OncoType DX assay) to further refine risk stratification for adjuvant chemotherapy for patients with node-negative, estrogen receptor-positive, HER2-negative breast cancers greater than 0.5 cm, whereas others do not (category 2B). The Panel overall continues to await the results of additional studies before a definitive recommendation may be made in the guideline on the role of the various genomic/gene expression array techniques in risk stratification and in the treatment decision making process.

Axillary lymph node positive tumors Patients with lymph node-positive disease are candidates for chemotherapy and, if the tumor is hormone receptor-positive, for the addition of endocrine therapy (category 1). In postmenopausal women, with hormone receptor-positive disease, an aromatase inhibitor should be utilized either as initial adjuvant therapy, sequential with tamoxifen, or as extended therapy following tamoxifen. In premenopausal women, adjuvant tamoxifen is preferred. If both chemotherapy and tamoxifen are used, data from the Intergroup trial 0100 suggest that delaying initiation of tamoxifen until after completion of chemotherapy improves disease-free survival compared with concomitant administration.120 Consequently, chemotherapy followed by endocrine therapy should be the preferred therapy sequence.

The paucity of clinical trial data regarding adjuvant chemotherapy in women over age 70 prohibits definitive recommendations in this age group. Adjuvant treatment in women over age 70 should be individualized, with consideration of comorbid conditions.

Guideline stratification for systemic therapy The current version of the Guidelines first recognizes subsets of patients with early breast cancer of the usual histologies based upon responsiveness to endocrine therapy and trastuzumab (ie, hormone receptor status, HER2 status) (see BINV-4). Patients are then further stratified based upon risk for recurrence of disease based upon anatomic and pathologic characteristics (ie, tumor grade, tumor size, axillary lymph node status, angiolymphatic invasion) (see BINV-5; BINV-6; BINV-7; BINV-8).

Adjuvant endocrine therapy The NCCN Guidelines call for the determination of estrogen and progesterone receptor content in all primary invasive breast cancers. Patients with invasive breast cancers that are estrogen or progesterone receptor positive should be considered for adjuvant endocrine therapy




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regardless of patient age, lymph node status, or whether or not adjuvant chemotherapy is to be administered.121 Selected studies suggest that HER2-positive breast cancers may be less sensitive to some hormonal therapies, although other studies have failed to confirm this finding.51,122-129 Given the inconsistency of these data and the favorable toxicity profile of the available endocrine therapies, the Panel recommends the use of adjuvant endocrine therapy in the majority of women with hormone receptor-positive breast cancer regardless of menopausal status, age, or HER2 status of the tumor. The exceptions to this recommendation are patients with lymph node-negative cancers less than or equal to 0.5 cm or 0.6 to 1.0 cm in diameter with favorable prognostic features where the prognosis is so favorable that the benefits of adjuvant endocrine therapy are very small.

The most firmly established adjuvant endocrine therapy is tamoxifen for both premenopausal and postmenopausal women.2 In women with estrogen receptor-positive breast cancer, adjuvant tamoxifen decreases the annual odds of recurrence by 39% and the annual odds of death by 31% irrespective of the use of chemotherapy, patient age, menopausal status, or axillary lymph node status.2 Prospective, randomized trials demonstrate that the optimal duration of tamoxifen appears to be five years. In patients receiving both tamoxifen and chemotherapy, chemotherapy should be given first, followed by sequential tamoxifen.120

Several studies have evaluated aromatase inhibitors in the treatment of postmenopausal women with early-stage breast cancer. These studies have utilized the aromatase inhibitors as initial adjuvant therapy, as sequential therapy following 2-3 years of tamoxifen, or as extended therapy following 4.5 -6 years of tamoxifen. The aromatase inhibitors are not active in the treatment of women with functioning ovaries and should not be used in women whose ovarian function cannot be reliably assessed owing to treatment-induced amenorrhea (see Definition of

Menopause, BINV-I). The results from two prospective, randomized clinical trials have provided early evidence of an overall survival benefit for patients with early-stage breast cancer receiving initial endocrine therapy with tamoxifen followed sequentially by anastrozole or exemestane when compared with tamoxifen as the only endocrine therapy.130,131 In addition, the National Cancer Institute Canada Clinical Trials Group (NCIC CTG) MA-17 trial demonstrated a survival advantage with extended therapy with letrozole compared with placebo in women with axillary lymph node-positive (but not lymph node-negative), estrogen receptor-positive breast cancer.132 Tamoxifen and aromatase inhibitors have different side effect profiles. Both contribute to hot flashes, night sweats and may cause vaginal dryness. Aromatase inhibitors are more commonly associated with musculoskeletal symptoms, osteoporosis, and increased rate of bone fracture, while tamoxifen is associated with an increased risk of uterine cancer and deep venous thrombosis.

Two studies have examined initial adjuvant endocrine treatment with either tamoxifen or an aromatase inhibitor. The Arimidex, Tamoxifen, Alone or in Combination Trial (ATAC Trial) demonstrated that anastrozole is superior to tamoxifen or the combination of tamoxifen and anastrozole in the adjuvant endocrine therapy of postmenopausal women with hormone receptor-positive breast cancer.133,134 With a median of 68 months follow-up, results in 9366 postmenopausal women with early breast cancer enrolled in the ATAC Trial demonstrated fewer recurrences (hazard ratio 0.87; 95% CI 0.78 - 0.97; P = 0.01) with anastrozole compared with tamoxifen. In the subset of women with hormone receptor-positive breast cancer the benefit was greater (hazard ratio 0.83; 95% CI 0.73 - 0.94; P =0.005).134 No difference in survival has been observed (hazard ratio 0.97; 95% CI, 0.85-1.12; P=0.7). A retrospective evaluation of the ATAC Trial data suggests that women with estrogen receptor-positive, progesterone receptor-negative breast cancer may experience a greater benefit




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favoring anastrozole than other hormone receptor combinations.135 Patients in the combined tamoxifen and anastrozole group gained no benefit over those in the tamoxifen group, suggesting a possible deleterious effect from the weak estrogenic effect of tamoxifen in patients with near complete elimination of endogenous estrogen levels. ATAC Trial sub-protocols show a lesser effect of anastrozole compared with tamoxifen on endometrial tissue,136 similar effects of anastrozole and tamoxifen on quality of life, with most patients reporting that their overall quality of life was not significantly impaired,137 a greater loss of bone mineral density with anastrozole,138 a small pharmacokinetic interference of anastrozole in the presence of tamoxifen of unclear significance,139 and no evidence for an interaction between prior chemotherapy and anastrozole.140

Breast International Group (BIG) 1-98 is a randomized trial testing the use of tamoxifen alone for 5 years, letrozole alone for 5 years, or tamoxifen for 2 years followed sequentially by letrozole for 3 years, or letrozole for 2 years followed sequentially by tamoxifen for 3 years. An early analysis compared tamoxifen alone versus letrozole alone, including those patients in the sequential arms during their first two years of treatment only.141 With 8,010 women included in the analysis, disease-free survival was superior in the letrozole treated women (hazard rate 0.81; 95% CI 0.70 – 0.93; log rank P=0.003). No interaction between progesterone receptor expression and benefit was observed. No difference in overall survival has been observed.

Four trials have studied the use of tamoxifen for 2-3 years followed sequentially by a third generation aromatase inhibitor versus continued tamoxifen. The Italian Tamoxifen Anastrozole (ITA) Trial randomized 426 postmenopausal women with breast cancer who had completed 2-3 years of tamoxifen to either continue tamoxifen or to switch to anastrozole to complete a total of 5 years of endocrine therapy.142 The hazard rate for relapse strongly favored sequential treatment with

anastrozole (hazard ratio 0.35; 95% CI, 0.18 - 0.68; P=0.001) with a trend towards fewer deaths (P=0.10).142 The Intergroup Exemestane Study (IES) trial randomized 4742 postmenopausal women with breast cancer who had completed a total of 2-3 years of tamoxifen to either continue tamoxifen or to switch to exemestane to complete a total of 5-years of endocrine therapy.143 The results at a median of 30.6 months of follow-up demonstrated the superiority of sequential exemestane in disease-free survival (hazard ratio 0.68; 95% CI 0.56 - 0.82; log rank P<0.001) with no difference in overall survival (hazard ratio 0.88; 95% CI 0.67 - 1.16; log rank P=0.37). Similar to the ATAC Trial, women with estrogen receptor-positive, progesterone receptor-negative breast cancer appeared to benefit to a greater degree in disease-free survival in comparison to other receptor subsets (hazard ratio in ER-positive, PR-negative 0.58; 95% CI 0.38 - 0.90; P not stated). However, results from the IES trial after 58 months of follow-up indicated that switching to exemestane was associated with statistically significant beneficial effects on both disease-free survival (hazard ratio 0.74; 95% CI 0.64-0.85; P<0.0001) and overall survival (hazard ratio 0.83).130 A prospectively planned, combined analysis of 3,224 patients enrolled in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 8 and the Arimidex Nolvadex® (ARNO 95) trial has also been reported.144 Patients in this combined analysis had been randomized following 2 years of tamoxifen to complete 5 years of adjuvant tamoxifen or to 3 years of anastrozole. With 28 months median follow-up available, event-free survival was superior with cross-over to anastrozole (hazard ratio 0.60; 95% CI 0.44-0.81; P=0.0009). No statistically significant difference in survival has been observed. An analysis of the ARNO 95 trial alone after 30.1 months of follow-up demonstrated that switching from tamoxifen to anastrozole was associated with significant increases in both disease-free survival (hazard ratio 0.61; 95% CI 0.40-0.93; P=0.023) and overall survival (hazard ratio 0.48; 95% CI 0.25-0.91; P=0.025).131




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Results of the MA-17 trial in 5187 women who had completed 4.5-6 years of adjuvant tamoxifen demonstrated that extended therapy with letrozole provides benefit in postmenopausal women with hormone receptor-positive, early breast cancer.132,145 At a median follow-up of 2.5 years, the results showed fewer recurrences or new contralateral breast cancers with extended letrozole (hazard ratio 0.58; 95% CI 0.45 - 0.76; P<0.001). No difference in overall survival was demonstrated (hazard rate 0.82; 95% CI 0.57-1.19; P=0.3), although there was a survival advantage in the subset of patients with axillary lymph node-positive disease (hazard rate 0.61; 95% CI 0.38-0.98; P=0.04). A formal quality of life analysis demonstrated reasonable preservation of quality of life during extended endocrine therapy, although women may experience ongoing menopausal symptoms and loss of bone mineral density.146,147

The differences in design and patient populations among the studies of the aromatase inhibitors do not allow for the direct comparison of the results of these studies. Thus, it is not known whether initial, sequential, or extended use of adjuvant aromatase inhibitors is the optimal strategy. The optimal duration of aromatase inhibitor treatment is also not known, nor is the optimal use vis-à-vis chemotherapy established. Further, the long-term (greater than 5 year) safety and efficacy of these agents are still under investigation. The various studies are consistent in demonstrating that the use of a third generation aromatase inhibitor in postmenopausal women with hormone receptor-positive breast cancer lowers the risk of recurrence, including ipsilateral breast tumor recurrence, contralateral breast cancer, and distant metastatic disease, compared to tamoxifen alone when the aromatase inhibitor is used as initial adjuvant therapy, sequential therapy, or extended therapy. Thus, the current version of the guideline recommends that postmenopausal women with early breast cancer receive an aromatase inhibitor as initial adjuvant therapy, sequential with tamoxifen, or as extended therapy in those situations where endocrine therapy is to be utilized. The guideline recommends the use of the specific aromatase inhibitor(s) that have

been demonstrated to be superior to tamoxifen alone in the specific clinical setting, although the Panel finds no compelling evidence that there are meaningful efficacy or toxicity differences between anastrozole, letrozole, and exemestane. In postmenopausal women, the use of tamoxifen alone for 5 years is limited to those who decline or who have a contraindication to aromatase inhibitors (see BINV-G).

It should be re-emphasized that the aromatase inhibitors are not active in women with functioning ovaries, and premenopausal women should not be given therapy with an aromatase inhibitor outside the confines of a clinical trial. Women who are premenopausal at the time of diagnosis and who become amenorrheic with chemotherapy may have continued estrogen production from the ovaries in the absence of menses. Serial assessment of circulating LH, FSH, and estradiol to assure a true postmenopausal status is mandatory if this subset of women are to be considered for therapy with an aromatase inhibitor148,149 (see BINV-I).

Adjuvant cytotoxic chemotherapy A number of combination chemotherapy regimens are appropriate to consider when adjuvant cytotoxic chemotherapy is utilized. These regimens include fluorouracil, doxorubicin, and cyclophosphamide (FAC/CAF) or cyclophosphamide, epirubicin, and fluorouracil (CEF); doxorubicin or epirubicin and cyclophosphamide (AC/EC); docetaxel, doxorubicin, and cyclophosphamide (TAC); doxorubicin or epirubicin followed by CMF; cyclophosphamide, methotrexate and fluorouracil (CMF); AC with sequential paclitaxel or docetaxel administered by a variety of schedules; doxorubicin, paclitaxel, cyclophosphamide each as a single agent for four cycles given every 2 weeks with filgrastim support (Dose-dense A – T– C); FEC followed by docetaxel; and docetaxel plus cyclophosphamide (TC). The current version of the guideline does not distinguish appropriate chemotherapy regimens by axillary lymph node status. Recent studies document substantial improvement in outcome with the incorporation of trastuzumab in the




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adjuvant treatment of HER2-positive breast cancer (see Adjuvant trastuzumab therapy). The guideline includes specific representative doses and schedules for the recommended adjuvant chemotherapy regimens (see BINV-H).

Studies of CMF chemotherapy versus no chemotherapy have shown disease-free and overall survival advantages with CMF chemotherapy.150 Studies using CAF/FAC (cyclophosphamide, doxorubicin, 5-fluorouracil) chemotherapy have shown that the use of full-dose chemotherapy regimens is important.151 In the Early Breast Cancer Trialists’ overview of polychemotherapy, comparison of anthracycline-containing regimens with CMF showed a 12% further reduction in the annual odds of recurrence (P = 0.006) and an 11% further reduction in the annual odds of death (P = 0.02) with anthracycline-containing regimens.150 Based on these data, the Panel qualified the appropriate chemotherapy regimens by the statement that anthracycline-containing regimens are preferred for node-positive patients. The Early Breast Cancer Trialists’ analysis, however, did not consider the potential interaction between HER2 tumor status and efficacy of anthracycline-containing versus CMF chemotherapy regimens. Retrospective analysis has suggested that the superiority of anthracycline-containing chemotherapy may be limited to the treatment of those breast cancers that are HER2-positive.50,52,125,152,153 The retrospective finding across several clinical trials that anthracycline-based chemotherapy may be more efficacious in patients whose tumors are HER2-positive,49,50,52,53,76 has led to a footnote stating that anthracycline-based chemotherapy may be superior to non-anthracycline-containing regimens in the adjuvant treatment of such patients (see BINV-H).

Doxorubicin and cyclophosphamide chemotherapy for 4 cycles has been studied in randomized trials, resulting in relapse-free and overall survival equivalent to CMF chemotherapy.154-156 No benefit from dose

escalation of either doxorubicin or cyclophosphamide was shown.157,158

A single study in women with 4 or more involved axillary lymph nodes compared the use of sequential versus alternating doxorubicin and CMF chemotherapy and found the sequential regimen superior.159,160

The results of two randomized trials comparing AC chemotherapy with or without sequential paclitaxel chemotherapy in women with axillary node-positive breast cancer suggest improved disease-free rates and results from one of the trials showed an improvement in overall survival with the addition of paclitaxel.158,161 On retrospective analysis, the apparent advantage of the paclitaxel-containing regimen appears greater in women with estrogen receptor-negative breast cancers.

A randomized trial evaluated the use of concurrent versus sequential chemotherapy (doxorubicin followed by paclitaxel followed by cyclophosphamide versus doxorubicin plus cyclophosphamide followed by paclitaxel) given either every two weeks with filgrastim support versus every three weeks. The results show no significant difference between the two chemotherapy regimens, but demonstrate a 26% reduction in hazard of recurrence (P=0.01) and a 31% reduction in the hazard of death (P=0.013) for the dose-dense regimens.162

Two randomized prospective trials of CEF chemotherapy in axillary lymph node-positive breast cancer are available. In one trial, premenopausal women with node-positive breast cancer were randomized to receive classic CMF therapy versus CEF chemotherapy using high-dose epirubicin. Both ten-year relapse-free survival (52% vs. 45%; P = 0.007) and overall survival (62% vs. 58%; P =0.085) favored the CEF arm of the trial.163 The second trial compared CEF given all intravenously every 3 weeks at 2 dose levels of epirubicin (50 mg/m2 vs. 100 mg/m2) in premenopausal and postmenopausal women with node-positive breast cancer. Five-year disease-free survival (55% vs. 66%; P =0.03) and overall survival (65% vs. 76%; P =0.007) both favored the epirubicin 100 mg/m2 arm.164 A recent trial compared 2




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dose levels of EC chemotherapy with CMF chemotherapy in women with node-positive breast cancer.165 This study showed that higher dose EC chemotherapy was equivalent to CMF chemotherapy and superior to moderate dose EC in event-free survival and overall survival. An additional randomized trial in women with axillary lymph node-positive breast cancer compared six cycles of FEC with three cycles of FEC followed by three cycles of docetaxel.166 Five-year disease-free survival (78.3% versus 73.2%, P=0.014) and overall survival (90.7% versus 86.7%, P=0.017) were superior with sequential FEC followed by docetaxel.

Final results from a randomized trial comparing docetaxel, doxorubicin, and cyclophosphamide (TAC) versus FAC chemotherapy in axillary lymph node-positive breast cancer demonstrated that TAC is superior to FAC.167 Estimated 5-year disease-free survival with TAC was 75% and FAC 68% (hazard ratio 0.72; 95% CI 0.59-0.88; P=0.001) and survival 87% with TAC and 81% with FAC (hazard ratio 0.70; 95% CI 0.53-0.91; P=0.008). Disease-free survival favored TAC in both estrogen receptor-positive and estrogen receptor-negative tumors.

The Eastern Cooperative Oncology Group E1199 study was a four arm trial that randomized 4,988 women to receive AC chemotherapy followed by either paclitaxel or docetaxel given by either an every three weekly schedule or a weekly schedule. With a median 46.5 months follow-up, no statistically significant differences in disease-free or overall survival have been observed when comparing the two taxanes or the two schedules of administration.168

Combination docetaxel and cyclophosphamide (TC) was compared with AC chemotherapy in a trial that randomized 1016 women with stage I – III breast cancer.169 Five-year disease-free survival was superior with TC compared with AC (86% versus 81%, P=0.027), but with no difference in overall survival (89% versus 88%, P=0.188).

Recent retrospective studies have evaluated the potential interaction of chemotherapy benefit and estrogen receptor status.2,119 These studies assessed the effect of chemotherapy on the risk of breast cancer recurrence in patients with estrogen receptor-positive tumors receiving adjuvant endocrine therapy when compared with patients with estrogen receptor-negative tumor status not undergoing adjuvant endocrine therapy. These analyses suggest that the benefits of chemotherapy are significantly greater in patients with estrogen receptor-negative disease. For example, the results of Berry et al. demonstrated that 22.8% more patients with estrogen receptor-negative tumors survived without disease for 5 years if they received chemotherapy; this benefit was only 7% for patients with estrogen receptor-positive tumors receiving chemotherapy.119 The guideline has therefore been modified to include a recommendation for endocrine therapy and consideration of chemotherapy for patients with node-negative disease and tumors characterized as estrogen receptor-positive which are greater than 1 cm and HER2-negative (see BINV-6). Previous versions of the guideline recommended the use of endocrine therapy plus chemotherapy in all such patients.

Adjuvant trastuzumab therapy Trastuzumab is a humanized, monoclonal antibody with specificity for the extracellular domain of the human epidermal growth factor receptor 2 (HER2/neu; HER2).170 Results of five randomized trials testing trastuzumab as adjuvant therapy were recently reported.55-58 In NSABP B-31 patients with HER2-positive, node-positive breast cancer were randomly assigned to 4 cycles of AC every three weeks followed by paclitaxel 4 cycles every three weeks or the same regimen with 52 weeks of trastuzumab commencing with the paclitaxel. In the North Central Cancer Treatment Group (NCCTG) N9831 trial, HER2-positive breast cancer that was node-positive, or, if node-negative, with primary tumors greater than 1 cm in size if ER and PR negative or greater than 2 cm in size if ER- or PR-positive, were similarly randomized except




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that paclitaxel was given by a low dose weekly schedule for 12 weeks and a third arm delayed trastuzumab until the completion of paclitaxel. The B-31 and NCCTG N9831 trials were jointly analyzed with the merged control arms for both trials compared with the merged arms using trastuzumab begun concurrently with the paclitaxel.55 There were 3,351 patients included in the joint analysis performed at 2 years median follow-up. A 52% reduction in the risk of recurrence (hazard ratio 0.48; 95% CI 0.39-0.59; log-rank P < 0.001) and a 33% reduction in the risk of death (hazard ratio 0.67; 95% CI 0.48-0.93; log-rank P = 0.015) were documented. Similar significant effects on disease-free survival were observed when results of the NSABP B-31 and NCCTG N9831 trials were analyzed separately. Cardiac toxicity was increased in patients treated with trastuzumab.55,171,172

A third trial (HERA) (N=5081) tested trastuzumab for one or for two years compared to none following all local therapy and a variety of standard chemotherapy regimens.56 At a median follow-up of one year, comparing one year versus not of trastuzumab, trastuzumab resulted in a 46% reduction in the risk of recurrence compared to no trastuzumab (hazard ratio 0.54; 95% CI 0.43-0.67; P < 0.0001), no difference in overall survival, and acceptable cardiac toxicity. The two year data are not yet reported.

The Breast Cancer International Research Group (BCIRG) 006 study randomized 3,222 women with HER2-positive, node-positive or high-risk node negative breast cancer to AC followed by docetaxel, AC followed by docetaxel plus trastuzumab for one year, or carboplatin, docetaxel plus trastuzumab for one year.57 At 23 months of follow-up, patients receiving AC followed by docetaxel with trastuzumab (AC DH) had a hazard ratio for disease-free recurrence of 0.49 (P=0.00000048) when compared with the group of patients in the control arm receiving the same chemotherapy regimen without trastuzumab (AC D). The hazard ratio for disease-free survival was

0.61 (P=0.00015) when patients in the carboplatin/docetaxel/ trastuzumab (TCH) containing arm were compared to patients in the control arm. No statistically significant difference in the hazard ratio for disease-free survival was observed between the two trastuzumab-containing arms. No survival data has been reported.

A fifth trial (FinHer) randomized 1010 women to either 9 weeks of vinorelbine followed by 3 cycles of FEC chemotherapy versus docetaxel for 3 cycles followed by 3 cycles of FEC chemotherapy.58

Patients (N=232) with HER2-positive cancers were further randomized to receive or not trastuzumab for 9 weeks during the vinorelbine or docetaxel portions of the chemotherapy only. With a median follow-up of 3 years, the addition of trastuzumab was associated with a reduction in risk of recurrence (hazard ratio 0.42; 95% CI 0.21-0.83; P=0.01). No statistically significant differences in overall survival (hazard ratio 0.41; 95% CI 0.16 – 1.08; P=0.07) or cardiac toxicity were observed with the addition of trastuzumab.

All of the adjuvant trials of trastuzumab demonstrate clinically significant improvements in disease-free survival, and the combined analysis from the NSABP B31 and NCCTG N9831 trials, demonstrated significant improvement in overall survival with the use of trastuzumab in patients with high-risk, HER2-positive breast cancer. Therefore, regimens from each of these trials are included as trastuzumab-containing adjuvant regimen choices in the guideline (category 1) (see BINV-H). The Panel recommends AC followed by paclitaxel with trastuzumab for 1 year commencing with the first dose of paclitaxel as the preferred trastuzumab-containing adjuvant regimen since the efficacy of this regimen has been demonstrated in two randomized clinical trials, and it has been associated with significant improvements in overall survival. Since patients with borderline FISH (Pathvysion®) scores of greater than 2.0 to 2.2 HER2 genes/chromosome 17/cell in early-stage breast cancer were eligible for the adjuvant trials, the Panel




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cannot recommend exclusion of these patients from adjuvant treatment with trastuzumab if HER2 tumor status remains equivocal following retesting by the same or a complementary method (see BINV-A).

In the adjuvant trastuzumab trials, the rates of grade III/IV congestive heart failure (CHF) or cardiac-related death for patients receiving treatment regimens containing trastuzumab ranged from 0% (FinHer trial) to 4.1% (NSABP B-31 trial) overall.55-58,171,172 The frequency of cardiac dysfunction appears to be related to both age and baseline left ventricular ejection fraction. The acceptable rate of significant cardiac toxicity observed in the trastuzumab adjuvant trials in part reflects rigorous monitoring for cardiac dysfunction.

Adjuvant therapy of favorable histology tumors The Guidelines provide systemic treatment recommendations for the favorable-histology invasive breast cancers, such as tubular and colloid cancers, based on tumor size and axillary lymph node status (see BINV-9). If used, the treatment options for endocrine therapy, chemotherapy, and sequencing of treatment with other modalities are similar to those of the usual histology breast cancers. The vast majority of tubular breast cancers are both estrogen receptor-positive and HER2-negative. Thus, the pathology evaluation and accuracy of the estrogen receptor and/or HER2 determination should be questioned if a tubular breast cancer is found to be estrogen receptor-negative and/or HER2-positive. The Panel acknowledges that prospective data regarding systemic adjuvant therapy of favorable histology tumors is lacking. Medullary carcinoma is an uncommon variant of infiltrating ductal carcinoma characterized by high nuclear grade, lymphocytic infiltration, a pushing tumor border, and the presence of a syncytial growth pattern. It was previously thought that medullary carcinoma has a lower potential for metastases and a better prognosis than typical infiltrating ductal carcinoma. However, the best available evidence suggests that the risk of metastases equals that of other high-grade

carcinomas, even for cases that meet all the pathologic criteria for typical medullary carcinoma. Furthermore, typical medullary carcinoma is uncommon, and there is marked interobserver variation in diagnosing this entity. Many cases classified as medullary carcinoma do not have all the pathologic features on subsequent pathologic review. Given these facts, there is concern that patients may be harmed if a high-grade infiltrating ductal carcinoma is misclassified as typical medullary carcinoma and this classification used as the basis for withholding otherwise indicated adjuvant systemic therapy. Therefore, the NCCN Panel believes that including medullary carcinoma with other special histology cancers that carry a very favorable prognosis and often do not require systemic therapy is not appropriate. The Panel recommends that cases classified as medullary carcinoma be treated as other infiltrating ductal carcinomas based on tumor size, grade, and lymph node status.

Stage III Invasive Breast Cancer The staging evaluation for patients with stage III invasive breast cancer is similar to the one for patients with stage I or stage II disease. The workup includes history and physical exam, a complete blood cell count, platelet count, a bone scan (category 2B), chest imaging, pathology review, pre-chemotherapy determination of tumor ER/PR receptor status and HER2 status, diagnostic bilateral mammogram and breast ultrasound as clinically warranted, and an abdominal CT, ultrasound, or MRI scan (category 2B), even in the absence of symptoms, liver enzyme abnormalities, or abnormal alkaline phosphatase.

Operable locally advanced breast cancer (clinical stage T3N1M0) Locally advanced breast cancer describes a subset of invasive breast cancer where the initial clinical and radiographic evaluation documents advanced disease confined to the breast and regional lymph nodes. The AJCC clinical staging system used in these Guidelines and for the




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determination of operability is recommended and locally advanced disease is represented by the stage III category. Patients with stage III disease may be further divided into those where an initial surgical approach is unlikely to be successful in removal of all disease or to provide long-term local control and those with disease where a reasonable initial surgical approach is likely to achieve pathologically negative margins and provide long-term local control. Thus, stage IIIA patients are divided into those who have clinical T3N1M0 disease versus those who have clinical TanyN2M0 disease, based on evaluation by a multidisciplinary team. For patients with operable locally advanced disease, generally patients with clinical T3N1M0 disease, treatment is as outlined in BINV-1 through BINV-6.

Postsurgical systemic adjuvant therapy for patients with stage IIIA breast cancer who do not receive neoadjuvant chemotherapy is similar to that for patients with stage II disease.

Inoperable locally advanced breast cancer (clinical stage IIIA [except for T3N1M0], clinical stage IIIB, or clinical stage IIIC) For patients with inoperable locally advanced disease at presentation, the initial use of anthracycline-based preoperative chemotherapy is standard therapy.173 Local therapy after preoperative therapy usually consists of (1) total mastectomy with axillary lymph node dissection, with or without delayed breast reconstruction, or (2) lumpectomy and axillary dissection. Both local treatment groups are considered to have sufficient risk of local recurrence to warrant the use of chest wall (or breast) and supraclavicular node irradiation. If internal mammary lymph nodes are involved, they should also be irradiated. In the absence of detected internal mammary node involvement, consideration may be given to including the internal mammary lymph nodes in the RT field.

Patients with an inoperable stage III tumor with disease progression during preoperative chemotherapy should be considered for palliative breast irradiation in an attempt to enhance local control. In all subsets

of patients, further systemic adjuvant chemotherapy after local therapy is felt to be standard. Tamoxifen (or an aromatase inhibitor if postmenopausal) should be added for those with hormone receptor-positive tumors or those with unknown hormone receptor status. Post-treatment follow-up for women with stage III disease is the same as for women with earlier-stage, invasive breast cancer.

Post-therapy Surveillance and Follow-up Post-therapy follow-up is optimally performed by members of the treatment team and includes the performance of regular physical examinations and mammography. In patients undergoing breast-conserving therapy, the first follow-up mammogram should be performed approximately 6 months after the completion of breast-conserving RT. The routine performance of alkaline phosphatase and liver function tests are not included in the Guidelines.174-176 In addition, the Panel notes no evidence to support the use of “tumor markers” for breast cancer, and routine bone scans, CT scans, MRI scans, PET scans, or ultrasound examinations in the asymptomatic patient provide no advantage in survival or ability to palliate recurrent disease and are, therefore, not recommended.177

The use of dedicated breast MRI may be considered as an option for post-therapy surveillance and follow-up in women at high risk of bilateral disease, such as carriers of BRCA 1/2 mutations. Rates of contralateral breast cancer following either breast-conserving therapy or mastectomy have been reported to be increased in women with BRCA 1/2 mutations when compared with patients with sporadic breast cancer.178-180 (see NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian Guidelines; NCCN Breast Cancer Screening and Diagnosis Guidelines).

The Panel recommends that women with intact uteri who are taking tamoxifen should have yearly gynecologic assessments and rapid




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evaluation of any vaginal spotting that might occur because of the risk of tamoxifen-associated endometrial carcinoma in postmenopausal women181 (see BINV-15). The performance of routine endometrial biopsy or ultrasonography in the asymptomatic woman is not recommended. Neither test has demonstrated utility as a screening test in any population of women. The vast majority of women with tamoxifen-associated uterine carcinoma have early vaginal spotting.

Symptom management for women on adjuvant endocrine therapies often requires treatment of hot flashes and the treatment of concurrent depression. Venlafaxine has specifically been studied and is an effective intervention in decreasing hot flashes.182 Recent evidence has suggested that concomitant use of tamoxifen with certain selective serotonin reuptake inhibitors (SSRIs) (eg, paroxetine and fluoxetine) may decrease plasma levels of endoxifen, an active metabolite of tamoxifen.183,184 These SSRIs may interfere with the enzymatic conversion of tamoxifen to endoxifen by inhibiting a particular isoform of cytochrome P-450 enzyme (CYP2D6) involved in the metabolism of tamoxifen. However, the SSRIs citalopram and venlafaxine appear to have only minimal effects on tamoxifen metabolism.

Premenopausal women who experience early ovarian failure secondary to adjuvant chemotherapy and postmenopausal women who are treated with an aromatase inhibitor are at increased risk for the development of osteopenia or osteoporosis with an associated increased risk of bone fracture. The guideline thus recommends monitoring of bone health during surveillance in these high risk women185 (see BINV-15).

A special situation arises in women who are premenopausal at diagnosis, who develop amenorrhea during or following treatment, and for whom the use of an aromatase inhibitor is considered. The continuation or return of ovarian function following chemotherapy with or without amenorrhea has been documented.148,149 If an aromatase

inhibitor is considered in women with amenorrhea following treatment, baseline levels of estradiol and gonadotropin followed by serial monitoring of these hormones should be performed if endocrine therapy with an aromatase inhibitor is initiated.149 (see BINV-I). Bilateral oophorectomy assures postmenopausal status in young women with therapy-induced amenorrhea and may be considered prior to initiating therapy with an aromatase inhibitor in a young woman.

Follow-up also includes assessment of patient adherence to ongoing medication regimens such as endocrine therapies. Predictors of poor adherence to medication include the presence of side effects associated with the medication, and incomplete understanding by the patient of the benefits associated with regular administration of the medication.186 The Panel recommends the implementation of simple strategies to enhance patient adherence to endocrine therapy, such as direct questioning of the patient during office visits, as well as brief, clear explanations on the value of taking the medication regularly and the therapeutic importance of longer durations of endocrine therapy (see BINV-15).

Stage IV Metastatic or Recurrent Breast Cancer The staging evaluation of women who present with metastatic or recurrent breast cancer includes history and physical exam, the performance of a CBC, platelet count, liver function tests, chest imaging, bone scan, radiographs of any long or weight-bearing bones that are painful or appear abnormal on bone scan, consideration of CT or MRI scan of the abdomen, biopsy documentation of first recurrence if possible, and determination of hormone receptor status (estrogen receptor and progesterone receptor) and HER2 status if not previously performed. Positron emission tomography (PET) scanning was added to the current guideline as an optional imaging procedure (category 2B). If performed, based on limited data, the Panel recommends that




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PET scanning not replace the performance of other more established imaging studies.187

Local disease only Patients with local recurrence only are divided into those who had been treated initially by mastectomy and those who had received breast-conserving therapy. Mastectomy-treated patients should undergo surgical resection of the local recurrence (if it can be accomplished without heroic surgery) and involved-field RT (if the chest wall was not previously treated or if additional radiotherapy may be safely administered). The use of surgical resection in this setting implies the use of limited excision of disease with the goal of obtaining clear margins of resection. Unresectable chest wall recurrent disease should be treated with RT if no prior RT has been given. Women whose disease recurs locally after initial breast-conserving therapy should undergo a total mastectomy. After local treatment, women with local recurrences should be considered for systemic chemotherapy or endocrine therapy.

The current Guidelines add, in the localized clinical scenarios of the treatment of recurrence/stage IV disease guideline (see BINV-16), the consideration of the addition of hyperthermia to irradiation for localized recurrences/metastasis (category 3). There have been several prospective randomized trials comparing RT to RT + hyperthermia in the treatment of locally advanced/recurrent cancers, primarily breast cancer chest wall recurrences.188,189 While there is heterogeneity among the study results, a recent series with strict quality assurance demonstrated a statistically significant increase in local tumor response and greater duration of local control with the addition of hyperthermia to radiation compared to radiation alone.189 No differences in overall survival have been demonstrated. Delivery of local hyperthermia is technically demanding and requires specialized expertise and equipment (eg, the monitoring of temperatures and management of

possible tissue burns). The Panel thus recommends that the use of hyperthermia be limited to treatment centers with appropriate training, expertise, and equipment. The addition of hyperthermia generated substantial discussion and controversy among the Panel and is a category 3 recommendation.

Systemic disease The treatment of systemic recurrence of breast cancer prolongs survival and enhances quality of life but is not curative. Therefore, treatments associated with minimal toxicity are preferred. Thus, the use of the minimally toxic endocrine therapies is preferred to the use of cytotoxic therapy whenever reasonable.

Women with bone metastasis, especially if lytic, should be given a bisphosphonate (eg, pamidronate or zoledronic acid) in combination with calcium citrate and vitamin D if expected survival is 3 months or longer and creatinine levels are below 3.0 mg/dL (category 1).185,190-195

Bisphosphonates are given in addition to chemotherapy or endocrine therapy. Zoledronic acid may be superior to pamidronate in lytic breast metastasis.196,197

Women considered to be appropriate candidates for initial endocrine therapy for recurrent or metastatic disease include those whose tumors are estrogen receptor- and/or progesterone receptor-positive, those with bone or soft tissue disease only, and those with limited, asymptomatic visceral disease.

In postmenopausal women with previous antiestrogen therapy and who are within one year of antiestrogen exposure, recent evidence supports the use of a selective aromatase inhibitor as the preferred first-line therapy for their recurrent disease.198,199 For postmenopausal women who are antiestrogen naive or who are more than 1 year from previous antiestrogen therapy, the aromatase inhibitors appear to have superior outcome compared with tamoxifen, although the




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differences are modest.200-204 Therefore, either tamoxifen or an aromatase inhibitor is an appropriate option in this setting.

In premenopausal women with previous antiestrogen therapy who are within 1 year of antiestrogen exposure, the preferred second-line therapy is either surgical or radiotherapeutic oophorectomy or leuteinizing hormone-releasing hormone (LHRH) agonists with or without an antiestrogen. In premenopausal women without previous exposure to an antiestrogen, initial treatment with an antiestrogen with or without a LHRH agonist is preferred.205

Many premenopausal and postmenopausal women with hormone-responsive breast cancer benefit from sequential use of endocrine therapies at the time of disease progression. Therefore, women whose breast cancers respond to an endocrine maneuver with either shrinkage of the tumor or long-term disease stabilization (clinical benefit) should receive additional endocrine therapy at the time of disease progression. Additional endocrine therapies for second-line and subsequent therapy are listed in the endocrine algorithm (see BINV-J). The antiestrogen fulvestrant recently became available for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer previously treated with an antiestrogen. Fulvestrant lacks the estrogen agonistic activity of tamoxifen and is well tolerated as a single monthly gluteal intramuscular injection. Fulvestrant appears to be at least as effective as anastrozole in patients whose disease progressed on previous endocrine therapy,206,207 and a recent reanalysis of these studies suggests a longer duration of response favoring fulvestrant.208 Endocrine therapies in postmenopausal women include selective, nonsteroidal aromatase inhibitors (anastrozole and letrozole); steroidal aromatase inhibitors (exemestane); pure anti-estrogens (fulvestrant); progestin (megestrol acetate); androgens (fluoxymesterone); and high-dose estrogen (ethinyl estradiol). In premenopausal women, therapies include LHRH agonists (goserelin

and luprolide); surgical or radiotherapeutic oophorectomy; progestin (megestrol acetate); androgens (fluoxymesterone); and high-dose estrogen (ethinyl estradiol). After second-line hormonal therapy, little high-level evidence exits to assist in selecting the optimal sequence of hormonal therapy.

Women with estrogen and progesterone receptor-negative tumors, symptomatic visceral metastasis, or endocrine therapy refractory disease should receive chemotherapy. A variety of chemotherapy regimens are felt to be appropriate, as outlined in the treatment algorithm (see BINV-K). Combination chemotherapy generally provides higher rates of objective response and longer time to progression, in comparison to single agent chemotherapy. Combination chemotherapy is, however, associated with an increase in toxicity, and is of little survival benefit.209-212 Thus, the Panel finds little compelling evidence that combination chemotherapy is superior to sequential single agents. Standard clinical practice is to continue first-line chemotherapy until progression. Adverse effects may require dose reduction and cessation of chemotherapy prior to disease progression. Limited information suggests that progression-free survival can be prolonged with the use of continuous chemotherapy versus shorter course chemotherapy.213,214

Due to the lack of overall survival differences, the use of prolonged versus shorter chemotherapy needs to be weighted against the detrimental effects of continuous chemotherapy on overall quality of life.

Preferred first-line chemotherapies thus include sequential single agents or combination chemotherapy. Among preferred first-line single agents, the Panel includes doxorubicin, epirubicin, pegylated liposomal doxorubicin, paclitaxel, docetaxel, capecitabine, vinorelbine (all category 2A), and gemcitabine (category 2B). Among preferred first-line combination regimens, the Panel includes cyclophosphamide, doxorubicin, and fluorouracil (FAC/CAF); fluorouracil, epirubicin, cyclophosphamide (FEC); doxorubicin, cyclophosphamide (AC);




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epirubicin, cyclophosphamide (EC); doxorubicin in combination with either docetaxel or paclitaxel (AT); cyclophosphamide, methotrexate, fluorouracil (CMF); docetaxel, capecitabine; gemcitabine, paclitaxel. Other active agents include cisplatin, carboplatin, etoposide orally, vinblastine, and fluorouracil by continuous infusion. As with endocrine therapy, sequential responses are often observed with chemotherapy, supporting the use of sequential single agents and combination chemotherapy regimens. The current guideline includes doses and schedules of representative chemotherapy single agents and combination regimens for metastatic breast cancer (see BINV-K).

A recent trial randomized 715 women with recurrent or metastatic breast cancer to first-line chemotherapy with paclitaxel with or without bevacizumab, a humanized monoclonal antibody against the vascular endothelial growth factor (VEGF).215 This trial documented superior progression-free survival (hazard ratio 0.51; 95% CI 0.43-0.62; log rank test P <0.0001) favoring bevacizumab plus paclitaxel compared with paclitaxel alone. Improvements observed in overall survival with the addition of bevacizumab have not reached statistical significance.

Patients with tumors that are HER2-positive may derive benefit from treatment with trastuzumab as a single agent or in combination with selected chemotherapeutic agents. The Panel recommends selecting patients for trastuzumab therapy who have tumors either positive for HER2 by FISH or 3+ by IHC. HER2 testing recommendations are described in the guideline (see BINV-A). Patients with tumors IHC 0 or 1+ for HER2 or FISH not amplified have very low rates of trastuzumab response, and therapy with trastuzumab is not warranted. Adequate standardization and validation of HER2 assays used in clinical practice outside high-volume central facilities is a concern, and data suggest that false-positive determinations are common in low-volume testing facilities.42,44,47,216

In patients with metastatic or recurrent breast cancer with HER2-positive tumors, trastuzumab as a single agent59,61 or in combination with selected chemotherapeutics60 may be considered. A single randomized trial demonstrates benefit from adding trastuzumab to paclitaxel chemotherapy in patients with IHC 2+ or 3+ for HER2.60 Early nonrandomized data are available supporting the addition of agents such as docetaxel, vinorelbine, and platinum compounds in combination with trastuzumab. The Panel believes the 27% frequency of significant cardiac dysfunction in patients treated with the combination of trastuzumab and doxorubicin/cyclophosphamide chemotherapy in the metastatic setting is too high for use of this combination outside the confines of a prospective clinical trial.60,217 The current guideline includes doses and schedules of representative chemotherapy single agents and regimens for use in combination with trastuzumab for metastatic breast cancer (see BINV-K).

Failure to achieve a tumor response to 3 sequential chemotherapy regimens or an Eastern Cooperative Oncology Group (ECOG) performance status of 3 or greater was believed to be an indication for supportive therapy only (category 2B). In this context, failure to respond to a chemotherapy regimen means the absence of even a marginal response to the use of a given chemotherapy regimen. Response to a chemotherapy regimen followed by progression of disease is not considered a failure to experience response.

Patients with metastatic breast cancer frequently develop a number of anatomically localized problems that may benefit from local irradiation, surgery, or regional chemotherapy (eg, intrathecal methotrexate for leptomeningeal carcinomatosis).




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Special Situations Paget’s Disease Paget’s disease of the breast is a rare manifestation of breast cancer characterized by neoplastic cells in the epidermis of the nipple areolar complex.218 It most commonly presents with eczema of the areola, bleeding, ulceration, and itching of the nipple. The diagnosis is often delayed because of the rare nature of the condition and confusion with other dermatologic conditions. There is an associated cancer elsewhere in the breast in up to 80% of cases.219,220 The associated cancers are not necessarily located adjacent to the nipple areolar complex and may be either ductal carcinoma in situ (DCIS) or invasive cancer.

Women with clinical signs that raise suspicion for Paget’s disease require a complete history and physical examination and diagnostic breast imaging (see PAGET-1). If no other breast lesion is identified, breast MRI may be considered before or after biopsy of the nipple areolar complex.221 Any breast lesion identified by imaging or examination should be evaluated according to the NCCN Breast Screening and Diagnostic Guidelines. The skin of the nipple areolar complex should undergo surgical biopsy including the full thickness of the epidermis including at least a portion of any clinically involved nipple areolar complex.

There are no category 1 data that specifically address local management of Paget’s disease. Systemic therapy is based on the stage and biological characteristics of any underlying cancer, and is supported by the evidence cited in the relevant stage-specific breast cancer treatment guidelines.

Management of Paget’s disease has traditionally been total mastectomy with axillary dissection. Total mastectomy remains a reasonable option for patients regardless of the absence or presence of

an associated breast cancer.219 Recent data demonstrate that satisfactory local control may be achieved with breast-conserving surgery including the excision with negative margins of any underlying breast cancer along with resection of the nipple areolar complex followed by whole breast radiotherapy.222-226 The risk of ipsilateral breast recurrence after breast-conserving nipple areolar complex resection and radiotherapy with or without an associated cancer is similar to that with breast-conserving surgery and radiotherapy with the typical invasive or in situ cancer.

For Paget’s disease without an associated cancer (ie, no palpable mass or imaging abnormality), it is recommended that breast-conserving surgery consist of removal of the entire nipple areolar complex with a negative margin of underlying breast tissue. In cases with an associated cancer elsewhere in the breast, the surgery includes removal of the nipple areolar complex with a negative margin, and removal of the peripheral cancer using standard breast-conserving technique to achieve a negative margin. It is not necessary to remove the nipple areolar complex and the peripheral cancer in continuity in a single surgical specimen or through a single incision. Mastectomy also remains an appropriate treatment option (see PAGET-2).

Axillary lymph node staging is not necessary for Paget’s disease without a detectable underlying cancer as this occurs predominantly in association with pure DCIS. In the presence of an underlying invasive breast cancer treated with breast-conserving surgery, axillary surgery should be performed according to the Surgical Axillary Staging guideline (see BINV-C). In cases treated by total mastectomy, sentinel node biopsy should be considered because the final pathology may reveal an invasive cancer in the mastectomy specimen and the mastectomy precludes subsequent sentinel node biopsy.

Patients treated with breast conservation should receive whole breast radiation. Extended field radiation to regional lymph nodes should be




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used in cases of an associated invasive breast cancer with involved lymph nodes as for any breast cancer as described in BINV-2. A radiation boost should be considered to the site of the resected nipple areolar complex and any associated resected cancer site, if applicable.

Women with an associated invasive cancer have substantial risk of developing metastases. Adjuvant systemic therapy should be administered according to the stage of the cancer. Women with Paget’s disease treated with breast conservation and without an associated cancer or those with associated DCIS should consider tamoxifen for risk reduction. Those with an associated invasive cancer should receive adjuvant systemic therapy based on the stage and hormone receptor status as outlined in BINV-4 to BINV-9.

Phyllodes tumors of the breast (also known as phylloides tumors, cystosarcoma phyllodes)

Phyllodes tumors of the breast are rare tumors comprised of both stromal and epithelial elements. Phyllodes tumors exist in benign, borderline, and malignant subtypes, although there is not uniform agreement on the criteria for assigning subtype or for predicting biological behavior.227 Subtype of phyllodes tumor appears less important for risk of recurrence than does the margin of tumor-free resection achieved by surgical treatment. Diagnosis of phyllodes tumors prior to excisional biopsy/lumpectomy is uncommon. Phyllodes tumors occur in an older age distribution than fibroadenoma, a younger age distribution than the invasive ductal and lobular cancers, and with a mean age in the 40’s.228 Phyllodes tumors often enlarge rapidly and are usually painless. Phyllodes tumors often appear on ultrasound and mammography as fibroadenomas, and fine needle aspiration cytology and even core needle biopsy are inadequate to reliably distinguish phyllodes tumors from fibroadenoma.228 Thus in the setting of a large or rapidly enlarging clinical fibroadenoma, excisional biopsy should be considered to pathologically exclude a phyllodes tumor. Patients with

the Li-Fraumeni Syndrome (germ line p53 mutation, see NCCN Genetic/Familial High Risk Assessment Guidelines) have an increased risk of phyllodes tumors.229 Local recurrences of phyllodes tumors are the most common site of recurrence. Most distant recurrences occur in the lung, and may be solid nodules or thin-walled cavities.

Treatment of phyllodes tumors is with local surgical excision with tumor free margins of 1 cm or greater. Lumpectomy or partial mastectomy is the preferred surgical therapy. Total mastectomy is necessary only if negative margins cannot be obtained by lumpectomy or partial mastectomy230 (see PHYLL-1). Since phyllodes tumors rarely metastasize to the axillary lymph nodes, surgical axillary staging or axillary lymph node dissection is not necessary unless the lymph nodes are pathologic on clinical examination.231 In those patients who experience a local recurrence, resection of the recurrence with wide tumor-free surgical margins should be performed (see PHYLL-2). Some members of the Panel recommend local radiation therapy of the remaining breast or chest wall following resection of a local recurrence, but this recommendation is controversial (category 3).232

While the epithelial component of most phyllodes tumors contains estrogen receptor (58%) and/or progesterone receptor (75%),233 endocrine therapy has no proven role in the treatment of phyllodes tumors. Similarly, there is no evidence that adjuvant cytotoxic chemotherapy provides benefit in reduction of recurrences or death. In the rare patient who experiences a systemic recurrence (usually in the lung), treatment should be as recommended in the NCCN Soft Tissue Sarcoma Guidelines.


Breast cancer occurring concurrent with pregnancy is an infrequent clinical event. In a California registry study, there were 1.3 breast cancers diagnosed per 10,000 live births.234 Unfortunately, breast cancer during pregnancy is most often axillary lymph node-positive and




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with larger primary tumor size. Histologically the tumors are poorly differentiated, more frequently estrogen and progesterone receptor-negative and approximately 30% are HER2-positive.235,236 The diagnosis is often delayed because neither the patient nor the physician suspects malignancy.

Evaluation of the pregnant patient with suspected breast cancer should include a physical examination with particular attention to the breast and regional lymph nodes. Mammogram of the breast with shielding can be done safely and the accuracy is reported to be greater than 80%.237 Ultrasound of the breast and regional lymph nodes can be used to assess the extent of disease and also to guide biopsy. Ultrasound has been reported to be abnormal in up to 100% of breast cancers occurring during pregnancy.237 Biopsies for cytologic evaluation of a suspicious breast mass may be done with a fine needle aspiration (FNA) of the breast and suspicious lymph nodes. However, the preferred technique is core needle biopsy. This provides tissue for histologic confirmation of invasive disease as well as providing adequate tissue for hormone receptor and HER2 analyses.

Staging assessment of the pregnant patient with breast cancer may be guided by clinical disease stage. For clinically node-negative T1-T2 tumors, a chest x-ray (with shielding), liver function and renal function assessment and complete blood count with differential is appropriate. In patients who have clinically node-positive or T3 breast lesions, in addition to the aforementioned, an ultrasound of the liver and consideration of a screening MRI of the thoracic and lumbar spine without contrast may be employed. The documentation of the presence of metastases may alter the treatment plan and influence the patient’s decision regarding maintenance of the pregnancy.

Assessment of the pregnancy should include a maternal fetal medicine consultation and review of antecedent maternal risks such as hypertension, diabetes and complications with prior pregnancies.

Documentation of fetal growth and development and fetal age by means of ultrasonographic assessment is appropriate. Estimation of the date of the delivery will help with systemic chemotherapy planning. In addition, maternal fetal medicine consultation should include counseling regarding maintaining or terminating pregnancy. Counseling of the pregnant patient with breast cancer should include a review of the treatment options which include mastectomy or breast-conserving surgery as well as the use of systemic therapy. The most common surgical procedure has been modified radical mastectomy. However, Kuerer et al. have shown that breast-conserving surgery is possible if radiation therapy can be delayed to the postpartum period.238

Sentinel lymph node biopsy with radioactive tracer (eg, technectium 99m sulfur colloid) should be safe. There are limited data with only case reports and estimations of fetal radiation dose.239,240 Isosulfan blue dye for sentinel node biopsy procedures is not recommended during pregnancy.

The indications for systemic chemotherapy are the same in the pregnant patient as in the non-pregnant breast cancer patient, although chemotherapy should not be administered at any point during the first trimester of pregnancy. The greatest experience in pregnancy has been with anthracycline and alkylating agent chemotherapy.241,242 Collected data of chemotherapy exposure in utero indicates that the first trimester has the greatest risk of fetal malformation.243,244 Fetal malformation risks in the second and third trimester are approximately 1.3%, not different than that of fetuses not exposed to chemotherapy during pregnancy. If systemic therapy is initiated, fetal monitoring prior to each chemotherapy cycle is appropriate. Chemotherapy during pregnancy should not be given after week 35 of pregnancy in order to avoid the potential for hematologic complications at the time of delivery. Recent data from a single institution prospective study indicate that FAC chemotherapy (5-FU 500 mg/m2 IV day 1 and 4, doxorubicin 50 mg/m2




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by IV infusion over 72 hours and cyclophosphamide 500 mg/m2 IV day 1) may be given with relative safety during the second and third trimesters of pregnancy.242 Ondansetron, lorazepam and dexamethasone can be used as part of the pre-chemotherapy antiemetic regimen. As reported by Gwyn et al., the median gestational age at delivery was 38 weeks, more than 50% of the patients had vaginal delivery and there have been no fetal deaths.

There are limited data on the use of taxanes during pregnancy.245 As a consequence they are not recommended for use during pregnancy. If taxane use is indicated clinically, it may be used in the post-delivery setting.

There are only two case reports of trastuzumab use during pregnancy.246,247 Both case reports indicated oligohydramnios with administration of trastuzumab. If trastuzumab is otherwise indicated, it should be administered in the postpartum period.

Endocrine therapy and radiation therapy are contraindicated during pregnancy. Endocrine therapy and radiation therapy, if indicated, should thus not be initiated until the post-partum period.

Communication between the oncologist and maternal fetal medicine specialist is essential at every visit and treatment decision point for the patient (see PREG-1).

Summary The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. In many situations, the patient and physician have the responsibility to jointly explore and select the most appropriate option from among the available alternatives.

With rare exceptions, the evaluation, treatment, and follow-up recommendations in these Guidelines are based on the results of past

and present clinical trials. However, there is not a single clinical situation in which the treatment of breast cancer has been optimized with respect to either maximizing cure or minimizing toxicity and disfigurement. Therefore, patient/physician participation in prospective clinical trials allows patients to not only receive state-of-the-art cancer treatment but also to contribute to improving the treatment of future patients.

Disclosures for the NCCN Breast Cancer Guidelines Panel At the beginning of each panel meeting to develop NCCN guidelines, panel members disclosed financial support they have received in the form of research support, advisory committee membership, or speakers' bureau participation. Members of the panel indicated that they have received support from the following: American Bioscience, Amgen, AstraZeneca, Breast Cancer Research Foundation, Bristol-Myers Squibb, Celgene, Dendreon, Department of Defense, Eli Lilly, Ethicon Endo-Surgery, Genentech, Genomic Health, GlaxoSmithKline, Glaxo Wellcome, Immunicon, Inc., Kosan Biosciences, Lance Armstrong Foundation, Lilly, MedImmune, Millennium, Myriad, NCI, Novartis, Oncotech, Pfizer, Precision Therapeutics, Inc., Rhone Pouloc Roher, Inc., Roche, Sanofi-Aventis, Susan G. Komen Breast Cancer Foundation, Taiho Pharmaceuticals, Varian Medical Systems, Veridex and Wyeth. Some panel members do not accept any support from industry. The panel did not regard any potential conflicts of interest as sufficient reason to disallow participation in panel deliberations by any member.

Version 2.2007, 03/28/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. REF-1



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204. Paridaens R, Therasse P, Dirix L, et al. First line hormonal treatment (HT) for metastatic breast cancer (MBC) with exemestane (E) or tamoxifen (T) in postmenopausal patients (pts) - A randomized phase III trial of the EORTC Breast Group [meeting abstract]. J Clin Oncol. 2004;22:14S (July 15 suppl). Abstract 515.

205. Klijn JG, Blamey RW, Boccardo F, et al. Combined tamoxifen and luteninizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol. 2001;19:343-353.

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209. Carrick S, Parker S, Wilcken N, et al. Single agent versus combination chemotherapy for metastatic breast cancer. Cochrane Database Syst Rev. 2005;2:CD003372.

210. Sledge GW, Neuberg D, Bernardo P, et al. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol. 2003; 21:588-592.

211. O’Shaughnessy J, Miles D, Vukelja S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin. Oncol. 2002;20:2812-2823..

212. Albain K, Nag S, Calderillo-Ruiz J, et al. Global phase III study of gemcitabine plus paclitaxel (GT) vs. paclitaxel (T) as frontline therapy for metastatic breast cancer. (MBC): First report of overall survival [meeting abstract]. J Clin Oncol. 2004;22:14s(July 15 suppl). Abstract 510.




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213. Muss HB, Case LD, Richards F, 2nd, et al. Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. The Piedmont Oncology Association. N Engl J Med. 1991:325 1342-1348.

214. Falkson G, Gelman R, Pandya K, et al. Eastern Cooperative Oncology Group randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete remission following induction treatment. J Clin Oncol. 1998;16:1669-1676.

215. Miller KD, Wang M, Gralow J, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). [meeting abstract]. Presented at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2005;Abstract 3.

216. Roche PC, Suman VJ, Jenkins RB, et al. Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831. J Natl Cancer Inst. 2002;94:855-857.

217. Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20:1215-1221.

218. Sakorafas GH, Blanchard K, Sarr MG, Farley DR. Paget's disease of the breast. Cancer Treat Rev. 2001;27:9-18.

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221. Frei KA, Bonel HM, Pelte MF, et al. Paget disease of the breast: findings at magnetic resonance imaging and histopathologic correlation. Invest Radiol. 2005;40:363-367.

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229. Birch JM, Alston RD, McNally RJ, et al. Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene. 2001;20:4621-4628.

230. Chaney AW, Pollack A, McNeese MD, et al. Primary treatment of cystosarcoma phyllodes of the breast. Cancer. 2000;89:1502-1511.

231. Mangi AA, Smith BL, Gadd MA, et al. Surgical management of phyllodes tumors. Arch Surg. 1999;134:487-492; discussion 492-483.

232. Pandey M, Mathew A, Kattoor J, et al. Malignant phyllodes tumor. Breast J. 2001;7:411-416.

233. Tse GM, Lee CS, Kung FY, et al. Hormonal receptors expression in epithelial cells of mammary phyllodes tumors correlates with pathologic grade of the tumor: a multicenter study of 143 cases. Am J Clin Pathol. 2002;118:522-526.

234. Smith LH, Dalrymple JL, Leiserowitz GS, et al.. Obstetrical deliveries associated with maternal malignancy in California, 1992 through 1997. Am J Obstet Gynecol. 2001;184:1504-1512; discussion 1512-1513.

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236. Gwyn K, Theriault R. Breast cancer during pregnancy. Oncology (Williston Park). 2001;15:39-46; discussion 46, 49-51.

237. Yang WT, Dryden MJ, Gwyn K, et al. Imaging of breast cancer diagnosed and treated with chemotherapy during pregnancy. Radiology. 2006;239:52-60.

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242. Johnson PH, Gwyn K, Gordon L, et al. The treatment of pregnant women with breast cancer and the outcomes of the children exposed to chemotherapy in utero [meeting abstract]. J Clin Oncol. 2005;23:16s(June 1 suppl). Abstract 540.

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245. Gonzalez-Angulo AM, Walters RS, Carpenter RJ, Jr., et al. Paclitaxel chemotherapy in a pregnant patient with bilateral breast cancer. Clin Breast Cancer. 2004;5:317-319.

246. Fanale MA, Uyei AR, Theriault RL, et al. Treatment of metastatic breast cancer with trastuzumab and vinorelbine during pregnancy. Clin Breast Cancer. 2005;6:354-356.




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247. Watson WJ. Herceptin (trastuzumab) therapy during pregnancy: association with reversible anhydramnios. Obstet Gynecol. 2005;105:642-643.

NCCN guidelines on Breast cancer

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